19374919

ELSEVIER

Pharmacology & Therapeutics journal homepage: www.elsevier.com/locate/pharmthera

Z

Pharmacology TH

.herapeutics

Associate editor: Graeme Eisenhofer

New targets and therapeutic approaches for endocrine malignancies

Martin Fassnacht ª,*, Michael C. Kreissl b, Dirk Weismann ª, Bruno Allolio ª

a Endocrine and Diabetic Unit, Department of Internal Medicine I, University Hospital, University of Würzburg, Germany

b Dept. of Nuclear Medicine, University Hospital, University of Würzburg, Germany

ARTICLE INFO

Keywords:

Thyroid carcinoma Parathyroid carcinoma Adrenocortical carcinoma Malignant pheochromocytoma

Targeted therapies Tyrosine kinase inhibitors

ABSTRACT

In endocrine malignancies (thyroid carcinoma, parathyroid carcinoma, adrenocortical carcinoma, malignant pheochromocytoma) surgery is currently the treatment of choice, in case of differentiated thyroid carcinomas followed by 131-I-radioiodine administration. This approach is often successful in early disease; however, treatment options for advanced endocrine malignancies remain unsatisfactory and prognosis is poor. In particular, cytotoxic chemotherapy and radiation therapy often show only limited and transient efficacy and are associated with significant toxicity. Thus, new treatment options are urgently needed. Advances in the understanding of the molecular pathology of endocrine malignancies has recently led to identification of key events in endocrine oncogenesis (e.g. oncogenic RET mutations in medullary thyroid carcinoma or RET/PTC rearrangements in papillary thyroid carcinoma). These new insights are increasingly matched by new compounds (e.g. tyrosine kinase inhibitors) targeting signaling pathways essential for tumor cell survival, proliferation and metastases. Accordingly, a rapidly growing number of preclinical investigations and early clinical trials in endocrine malignancies have been initiated. First results of “targeted therapies” in medullary and differentiated thyroid carcinoma are impressive: phase II trials targeting RET or VEGF receptor kinases led to objective tumor response in up to 50% of patients. This review covers these recent molecular and clinical advances which most likely will dramatically alter the treatment of endocrine malignancies within the coming decade.

@ 2009 Elsevier Inc. All rights reserved.

Contents

1.	Introduction	118
2.	Differentiated thyroid carcinoma and anaplastic thyroid carcinoma.	119
3.	Medullary thyroid carcinoma	124
4.	Parathyroid carcinoma.	127
5.	Adrenocortical carcinoma	128
6.	Malignant pheochromocytoma/paraganglioma	131
7.	Conclusions	133
	References	134

Abbreviations: ACC, adrenocortical carcinoma; ATC, anaplastic thyroid carcinoma; AZT, azidothymidine; bFGF, basic fibroblast growth factor; BRAF, V-raf murine sarcoma viral oncogene homolog B1; BWS, Beckwith-Wiedemann Syndrome; CEA, carcinoembryonic antigen; COX-2, cyclooxygenase-2; CR, complete response; DPTPA, diethylenetriaminepenta- acetic acid; DTC, differentiated thyroid carcinoma; EGFR, epidermal growth factor receptor; FTC, follicular thyroid cancer; GDNF, glial cell line-derived neurotrophic factor; GFLs, GDNF-family ligands; HAT, histone acetylase; HDAC, histone deacetylase; HSP90, heat shock protein 90; IGF, insulin like growth factor; IKBa, inhibitor protein I K B alpha-associated protein kinase; JNK, Jun NH2-terminal protein kinase; LOH, loss-of-heterozygosity; mAB, monoclonal antibody; MAPK, mitogen-activated protein kinase; MEN, multiple endocrine neoplasia; MTC, medullary thyroid carcinoma; NFKB, nuclear factor K B; nM, nanomolar; p18-INK4c, cyclin dependent kinase 4 inhibitor C; PD, progressive disease; PDGFRB, platelet- derived growth factor receptor B; PI3K, phosphatidylinositol 3-kinase; PIGF, placenta growth factor; PR, partial response; PPARy, peroxisome proliferator activator receptor y; PTC, papillary thyroid carcinoma; PTEN, phosphatase and tensin homolog; RAR, retinoic acid receptors; RET, “REarranged during Transfection”-proto-oncogene; RTK, receptor tyrosine kinase; RXR, retinoid X receptor; SD, stable disease; SDHB, succinate dehydrogenase subunit B; SDHD, succinate dehydrogenase subunits D; SSR, somatostatin receptor; TERT, human telomerase; TK, tyrosine kinase; TKI, tyrosine kinase inhibitors; VCP, valosin-containing protein; VEGF, vascular endothelial growth factor; VEGF-R, vascular endothelial growth factor receptor; VHL, von Hippel-Lindau.

# This study was supported by grants of the Deutsche Krebshilfe (# 106 080 to B.A. and M.F. and grant # 107111 to M.F.) and the German Ministry of Research BMBF (#01KG0501 to B.A. and M.F.).

* Corresponding author. Endocrine and Diabetic Unit, Department of Internal Medicine I, University Hospital of Wuerzburg, Josef-Schneider-Str. 2, D-97080 Würzburg, Germany. Tel .: +49 931 201 36507; fax: +49 931 201 36766.

E-mail address: fassnacht_m@medizin.uni-wuerzburg.de (M. Fassnacht).

1. Introduction

Most endocrine malignancies are rare tumors deriving from the endocrine cells throughout the body. In contrast to prolactinomas that served - due to their response to dopamine agonists - for many years as paradigmatic tumors for a targeted therapy, the majority of malignant endocrine tumors are not (yet) accessible for a specific therapy. In this review, we give an overview of new treatment options for thyroid carcinoma (differentiated, anaplastic, and medullary), parathyroid carcinoma, adrenocortical carcinoma, and malignant pheochromocytoma. To keep the article focused, we do not cover gastrointestinal neuroendocrine tumors, testicular or ovarian cancer, and hormone-dependent tumors.

With exception of differentiated thyroid carcinoma (DTC) the overall prognosis of these endocrine tumors is poor. Surgery is standard therapy in all these malignancies. In some tumor entities like DTC specific radionuclide therapy is established as the next ther- apeutic step. In advanced stages, however, treatment is not standar- dized and systemic therapy for metastatic endocrine tumors have been described as poorly effective. Despite (or perhaps because of) limited efficacy of cytotoxic chemotherapy, results from only few prospective trials of new drugs or combinations of drugs were published during the latter half of the twentieth century. During the past 15 years, several opportunities have arisen that have led to a relative plethora of clinical trials testing novel therapies for solid tumors. Of prime importance has been the discovery of specific key etiologic, oncogenic mutations in cancer cells and in recent years, increasing insights were also gained in the pathophysiology of endocrine tumors. Many of these developments are related to “classical” intracellular signaling pathways (Fig. 1). In addition, progress was made in the understanding of physiologic processes that facilitate tumor growth, either reflecting abnormalities such as epigenetic modifications of chromosomal DNA and histones or normal adaptations as e.g. hypoxia-inducible angiogenesis. Furthermore, the critical role of the tumor microenvironment (“tumor stroma”) has

become clearer. Angiogenesis is of key importance for tumor growth and metastasis formation (Carmeliet & Jain, 2000; Kerbel, 2008). Therefore, there is increasing interest in the development of anti- angiogenetic drugs. Since endocrine malignancies are often highly vascularized, this approach is particularly attractive for these tumors. In addition, drugs against specific signaling pathways like the RET- Ras-Raf-MAP or the protein kinase B pathway might be attractive also for endocrine tumors. Although development and investigations of new drugs are still in a very early stage for most endocrine tumors, we aim to give a perspective on the rapidly growing opportunities in the near future.

To reduce redundancy, we summarize the new drug classes in the beginning. The targets of these drugs fall into the following categories: (i) targets on the cell surface; (ii) targets involved in intracellular signaling pathways, (iii) targets in the cell nucleus, (iiii) targets on tumor vessels and peritumoral cells. Most of the new drugs act on one or several of these target categories. Although many of these drugs are so called targeted therapies, there is increasing evidence that most of these drugs (especially kinase inhibitors) are not as specific as initially proposed.

Monoclonal antibodies (mAB) have emerged as a class of novel oncology therapeutics since end of the 1970s, when Köhler and Milstein described a technique of somatic cell hybridization (Kohler & Milstein, 1975). To avoid immunogenicity and to increase the activity of the mAbs, new chimeric and humanized mAbs were generated. The anticancer effects of these antibodies derive from blockade of growth factor/receptor interaction and/or down-regulation of oncogenic proteins on the tumor cell surface (Table 1). All clinically used antibodies are administered intravenously.

Kinase inhibitors are usually orally available small molecules targeting specific signaling kinases. In general, these drugs are capable of inhibiting one or several kinases, often also directly affecting multiple downstream signaling pathways (Table 2). In contrast to antibodies the vast majority of these small molecules act intracellu- larly. Most small-molecule kinase inhibitors obstruct the binding site

Fig. 1. Simplified scheme of selected signaling pathways and potential therapeutic targets for endocrine tumors (modified according to Coelho et al., 2007).

Growth factors like VEGF, PDGF etc.

Kinase inhibitors

Antibodies (e.g. against VEGF)

PTEN

PI3 Kinase

P

P

RAC

RAS

Farnesyl transferase inhibitors

RAF inhibitors Hsp90 inhibitors

AKT inhibitors

AKT

RAF

JUN

mTOR inhibitors

MEK

MEK inhibitors

IKB NFKB

mTOR

HIF

ERK

Histone deacetylase inhibitors Retinoic acid

IKK inhibitors IKB degradation inhibitors

Phosphorylation of transcription factors

Gene transcription

Table 1 Monoclonal antibodies and other targeted therapies used in endocrine tumors.ª

Agent	Target	Pre-clinical studiesb	Clinical experienceb
Bevacizumab“	VEGF	ATC	ACC
Bexarotene	RXR	DTC	DTC
Bortezomib (PS-341)	IKBa	ATC
Celecoxib“	COX-2	DTC	DTC
Cetuximab“	EGFR	ATC
Combretastatin	VE-Cadherin + microtubules	ATC	ATC
CP-751,871	IGF-1	ACC
IMC-A12	IGF-1	ACC
Somatostatin	SSR	DTC, MTC, Pheo	ATC, DTC,
analogues“			MTC, Pheo
Thalidomide“	VEGF, bFGF		ACC, DTC, MTC
Thiazolidinediones“	PPARY	ACC, DTC	DTC
Trastuzumab“	HER2neu	ACC
Vorinostat	Histone deacetylase	ATC, DTC	DTC

a Kinase inhibitors see Table 2.

b Details see text.

” FDA and EMEA approved for other disease.

for ATP within the catalytic domain, thus, they can be described as ATP mimetics. Other compounds target the substrate binding site. All kinase inhibitors prevent autophosphorylation and signal transduc- tion. After oral administration, nanomolar serum levels are achieved that are sufficient to inhibit the target kinase (Table 2).

In addition to antibodies and kinase inhibitors several other types of drugs (e.g. proteosome inhibitors) are under development (Table 1).

Adverse effects of “targeted therapies”. In general, molecular- targeted therapies are relatively well tolerated when compared with cytostatic drugs; however, some patients are exquisitely sensitive to develop particular and sometimes severe toxicities, which are generally explained by effects of kinase inhibition in non-neoplastic cells. The typical side-effects of antibodies and small molecules are different from cytotoxic agents. Common side effects include hypertension, diarrhea, skin lesions, and fatigue. Since these adverse effects are drug related and not tumor entity specific we will not cover these aspects in detail in our review (for review see de Castro & Awada, 2006; Widakowich et al., 2007). Of note, several kinase inhibitors influence the endocrine system; especially thyroid function and thyroid hormone metabolism.

Immunotherapy has been discussed controversially but recent advances seem to promote a renaissance of this treatment modality (Finn, 2008; Weiner, 2008). Therapeutic approaches include immune modulating antibodies and therapies using primed dendritic cells or transfer of modified T cells.

Radionuclide therapy targeting the sodium-iodine-symporter has been successfully used in treating thyroid carcinoma for decades. Of

historical note, this approach is one of the first molecular targeted therapies and has been used long before this vogue term has been coined. Meanwhile, many new targets have been identified, leading to therapeutic options also for tumors other than differentiated thyroid carcinoma. One of the most promising targets is the somatostatin receptor. A particular advantage of radionuclides is the assessment of biodistribution prior to therapy by radionuclide imaging leading to reduced toxicity.

2. Differentiated thyroid carcinoma and anaplastic thyroid carcinoma

Differentiated thyroid carcinoma (DTC) is the most common endocrine malignancy. The diagnosis of this carcinoma has risen dramatically by 240% between 1950 and 2000 (Sosa & Udelsman, 2006). According to the American Cancer Society in 2006, thyroid carcinoma became the sixth most diagnosed cancer in women (Jemal et al., 2008). The reason for this increase is likely multifactorial and is not entirely understood. Increased detection of incidental thyroid nodules on radiological studies ordered for other reasons accounts in part for the rise in smaller carcinomas. In addition, a number of adults received head and neck irradiation as children for benign conditions, a procedure now known to increase both benign and malignant thyroid nodules.

DTC includes papillary (PTC; ~ 80% of DTC) and follicular (FTC; 10- 15%) subtypes as well as (oxyphilic) Hurthle cell carcinoma (<5%) (Hundahl et al., 1998; Busnardo & De Vido, 2000). They comprise 90% of all cases of thyroid carcinoma (Sherman, 2003). The overall prognosis for DTC is excellent; with a 10-year survival of >90%. Unfortunately once DTC has metastasized to distant sites and is no longer amenable to radioactive iodine therapy or surgery, expected survival declines rapidly (Ruegemer et al., 1988; Shoup et al., 2003).

In contrast, anaplastic thyroid carcinoma (ATC) is rare comprising only 1-2% of thyroid malignancies. However, it is one of the most lethal human malignant tumors, accounting for about 50% of all thyroid carcinoma deaths (Hundahl et al., 1998; Kitamura et al., 1999; Are & Shaha, 2006). ATC usually derives from pre-existing PTC or FTC. It usually presents as a rapidly growing neck mass, frequently associated with vocal cord paralysis, dyspnea and/or dysphagia. ATC typically has a rapid and devastating clinical course with a median survival <6 months.

2.1. Current treatment standards

Most expert groups advocate total or near-total thyroidectomy as the surgical procedure of choice in DTC (Cooper et al., 2006; Pacini et al., 2006). Additionally central cervical lymph node dissection has been recommended in all cases of papillary and Hurthle cell thyroid cancer); depending on the tumor stage or known lymphogenic spread, the removal of lymph nodes in the lateral neck may be

Table 2 Selection of kinase inhibitors recently used in clinical trials for endocrine tumors and their respective targets.

Agent	VEGFR1	VEGFR2	VEGFR3	RET	BRAF	PDGFRØ	EGFR	C-KIT	Others	Refs	Clinically tested in endocrine tumorsª
	IC50(nM)
Axitinib (AG013736)	1.2	0.25	0.29			2.5		1.7		Inai et al., 2004	ATC, DTC, MTC
E7080	22	4.0	5.2			39	6500	5.2		Matsui et al., 2008b	MTC
Erlotinibb (OSI-774)							20			Moyer et al., 1997	ACC
Gefitinibb (ZD1839)							33			Wakeling et al., 2002	ACC, ATC, DTC, MTC
Imatinibb (STI571)		>10,000		3700		100		150	BCR-ABL 25	Buchdunger et al., 2002	ACC, ATC, DTC, MTC
Motesanib (AMG706)	2	3	6	59		84		8	FLT3 33	Polverino et al., 2006	DTC, MTC
Sorafenibb (BAY43-9006)		90	20	47	22	57		68	P38-MAPK 38	Wilhelm et al., 2004	ATC, DTC, MTC, Pheo
Sunitinibb (SU011248)	2	4-9	17	41-100		2		1-10	FLT3 8-14	Kim et al., 2006; Chow & Eckhardt, 2007	MTC, Pheo
Vandetanib (ZD6474)	1600	40	110	130			500			Wedge et al., 2002; Herbst et al., 2007	MTC
XL184		0.035		4		234			C-MET 1.8	Sherman, 2008	MTC

a

Details see text.

b FDA and EMEA approved for other tumor entities.

indicated (Cooper et al., 2006). Radioiodine treatment with 131I is usually the next step in DTC management (Cooper et al., 2006; Luster et al., 2008). The goal is to destroy normal cells in the thyroid remnant and residual occult cancer cells. In order to ascertain sufficient uptake of 131I into thyroidal remnants and cancer cells TSH stimulation is required. Therefore, thyroid hormone medication has to be withdrawn for several weeks resulting in hypothyroidism with significant negative impact on quality of life (Dow et al., 1997; Luster et al., 2005a). An alternative is to administer recombinant TSH for the delivery of therapeutic or diagnostic 131I (Robbins et al., 2001; Berg et al., 2002; Barbaro et al., 2003; Luster et al., 2005b). Furthermore the whole body radiation dose is reduced using recombinant TSH as compared to endogenous stimulation after thyroid hormone with- drawal (Hanscheid et al., 2006). Post-therapeutic or diagnostic whole body imaging, especially when combined with determinations of thyroglobulin, is a valuable staging tool with a high specificity and sensitivity in detecting recurrence, locoregional and distant metas- tases (Sherman et al., 1994; Robbins et al., 2001). As an alternative, especially for intermediate or low risk patients, many centers use serum thyreoglobulin levels after stimulation with recombinant TSH to identify patients with persistent or recurrent tumor. Neck ultrasound has been proven to be an essential staging tool in DTC patients (Pacini et al., 2003; Cooper et al., 2006; Pacini et al., 2006) and may be complemented by conventional imaging and PET.

Because DTC is TSH-dependent, TSH-suppressive therapy with thyroid hormone is the third step in initial DTC management. Several series have shown decreased recurrence rates and cancer-related mortality with thyroid hormone suppression therapy in high-risk patients (Biondi et al., 2005). The use of TSH-suppressive therapy in low-risk patients however remains controversial, as clinical studies have failed to show a clear benefit (Cooper et al., 1998).

Depending on the course of the disease additional treatments with radioiodine may become necessary. As long as metastases and recurrences are radioiodine-avid those treatments are the most effective option and high response rates are achievable (Ronga et al., 2004). Depending on the site of metastatic disease, surgery and/or external beam radiotherapy may be considered.

Only few differentiated tumors display no uptake of radioiodine at presentation. However in up to 5% of cases, cellular dedifferentiation occurs during tumor progression leading to loss of iodide uptake, making the tumor resistant to radioiodine treatment. This is usually accompanied by more aggressive tumor growth and metastatic spread. Efforts have been made to reestablish radioiodine uptake using retinoic acid. Despite promising pre-clinical (Van Herle et al., 1990; Schreck et al., 1994; Schmutzler et al., 1996, 1997; Kurebayashi et al., 2000; Jeong et al., 2006) and initial clinical studies (Grunwald et al., 1998; Simon et al., 2002; Gruning et al., 2003; Coelho et al., 2004; Wiseman et al., 2008), tumor regression or stabilization is only seen in 20% of cases or even less (Simon et al., 2002; Gruning et al., 2003; Coelho et al., 2004; Short et al., 2004).

Once surgery, radioiodine treatment, and external beam radiation fail to cure or stabilize recurrence or metastatic disease, no therapy is established. The 10-year survival rate for patients with radioiodine- resistant metastatic disease is <15% (Durante et al., 2006). Commonly, systemic cytotoxic therapy is used in this setting, but low response rates and high toxicity limit its utility. The most frequently prescribed cytotoxic agent doxorubicin, leads to tumor response rates of 0%-22%; but these responses are usually partial and transient (Baudin & Schlumberger, 2007). A small increase in response rate has been observed if cisplatin is added to the regimen, however at the price of more severe side effects (Shimaoka et al., 1985). Therefore, patients with metastatic disease unresponsive to or unsuitable for radioiodine, surgery and external radiation therapy, are only treated with cytotoxic chemotherapy when they become symptomatic or rapidly progressive.

In ATC curative treatment is highly unlikely. Already at the time of primary diagnosis the tumor is usually unresectable due to its high

propensity for invading surrounding tissues. Due to the lack of iodine uptake into ATC cells radioiodine therapy is no option. Standard treatment of ATC consists of surgery, chemotherapy, and radiotherapy. Multimodal therapy, combining all these options, is recommended and seems to improve survival (Ain, 1999; Tennvall et al., 2002; Pasieka 2003; De Crevoisier et al., 2004). Due to the rarity and the aggressiveness of ATC large trials are difficult to implement. Hence a standardized successful protocol is lacking and the optimal sequence of multimodal therapy is still under discussion (Vini & Harmer, 2002; Kihara et al., 2004). Local control is a major component in treating ATC patients and surgical debulking followed by combined chemora- diotherapy (e.g. with doxorubicin, paclitaxel, vincristin or cisplatin), has been proposed as best option (Haigh et al., 2001; Sugino et al., 2002; De Crevoisier et al., 2004). However, also neo-adjuvant radiotherapy combined with chemotherapy followed by surgery has been suggested as alternative treatment option for ATC (Tennvall et al., 2002).

2.2. Molecular targets in differentiated and anaplastic thyroid carcinoma

DTC belongs to the neoplasms which have been extensively characterized genetically. Tumor-initiating events have been identi- fied in a high proportion of cases of DTC. Most of these events converge in a single signaling pathway, the mitogen-activated protein kinase (MAPK) pathway (Fig. 1). Activation of this pathway leads to cell growth and proliferation. Mutations in the signaling kinases BRAF and RAS as well as the RET/PTC rearrangement lead to constitutive activation of down-stream signaling via the MAPK pathway. Interest- ingly RET, BRAF, and RAS mutations rarely coexist in the same carcinoma, suggesting that any one of these abnormalities is sufficient to cause tumorigenesis (Trovisco et al., 2006).

In PTC, mutations in the BRAF kinase or a RET/PTC rearrangement can be observed in the majority of cases (Kimura et al., 2003; Fagin, 2005). BRAF mutations, specifically the BRAF-V600E mutation, are the most common genetic aberration seen in adult sporadic PTC (Fagin, 2004; Trovisco et al., 2006) and may be associated with lack of radioiodine responsiveness, more aggressive disease and poor out- come (Xing, 2005; Elisei et al., 2008; Romei et al., 2008). In cell culture, suppression of the BRAF/MEK/MAP kinase pathway in cells harboring the BRAF-V600E mutation has been shown to restore the expression of iodide-metabolizing genes (Liu et al., 2007).

Many different RET/PTC rearrangements have been described, each constituting a fusion of the RET with entirely different genes. However, no difference in clinical behavior has been observed (Fagin, 2004; Erdogan et al., 2008). The rearrangement can be detected in around 30% of cases and in over 60% of post-Chernobyl thyroid carcinomas (Rabes et al., 2000). It is frequently found in micro- carcinomas supporting the notion that this mutation is an early event in tumorigenesis (Sugg et al., 1998). Both, the RET/PTC1 and the RET/ PTC2 rearrangement induce COX-2, which in turn might be a possible target for drugs. The RET/PTC rearrangement is not commonly found in ATC. In a series of 20 cases, it was found in only 3 tissue samples, 2 of which also contained PTC tissues (Liu et al., 2008a).

Activating point mutations in the RAS oncogene occur in only about 10% of PTC, mainly in the follicular variant (Di Cristofaro et al., 2006). In contrast, in FTC up to 50% of cases are associated with mutations in the RAS oncogene (Garcia-Rostan et al., 2003; Vasko et al., 2003; Fukushima & Takenoshita, 2005). In these tumors, activation of RAS occurs through activating mutations in genes encoding RAS or through activation of upstream regulators. Mutations in all the three RAS oncogenes (H-RAS, K-RAS, and N-RAS) have been reported in thyroid carcinoma. An aggressive tumor phenotype and a worse prognosis have been associated with these mutations (Garcia- Rostan et al., 2003). In ATC, RAS mutations have been reported in variable frequency ranging from 6% to 50% (Garcia-Rostan et al., 2003; Fukushima & Takenoshita, 2005; Quiros et al., 2005; Hou et al., 2007;

Costa et al., 2008; Liu et al., 2008a; Santarpia et al., 2008). Of note, RAS mutations are also found in up to 2% of follicular adenomas (Esapa et al., 1999).

Besides the MAPK pathway, alterations in the PI3K/AKT pathway (Fig. 1) have frequently been detected in human cancer. Activation of AKT plays a pivotal role in cell proliferation and survival by regulating the function of many cellular proteins. Constitutive activation of the PI3K/AKT pathway occurs due to mutations or amplification of the PIK3CA gene encoding PI3K or the AKT gene, or as a result of inactivating mutations of inhibitors of the pathway (e.g. PTEN). The first evidence of the implication of this pathway in thyroid tumors was provided by Cowden disease. Germline mutations of the PTEN gene confer predisposition to Cowden disease, a condition characterized by development of hamartomas in multiple organs, multinodular goiter and thyroid adenomas, and increased risk of thyroid (mostly of the follicular type), breast and other carcinomas (Liaw et al., 1997; Eng, 1998). The potential relevance of this pathway in tumorigenesis is also supported by the high rate of PTEN promoter hypermethylation found in both PTC and FTC (Alvarez-Nunez et al., 2006). In addition, PTEN mutations have been observed in 17% of 48 cases of ATC (Liu et al., 2008a). In general, AKT expression and activation is increased in thyroid carcinomas, particularly in FTC (Ringel et al., 2001; Vasko et al., 2004), but also in ATC (Garcia-Rostan et al., 2005; Santarpia et al., 2008). In a recent study an association of PTEN promoter hypermethylation with alterations on the PI3K/AKT pathway was observed in FTC and ATC (Hou et al., 2008). As for the MAPK pathway a mutual exclusivity has been shown for genetic alterations in the PI3K/ AKT pathway in thyroid tumors (Wang et al., 2007). Therefore, specific inhibition of the activation of AKT may be a valid approach to treating thyroid malignancies, particularly FTC and ATC.

Somatic rearrangement in some DTC results in the fusion of PAX-8 to PPARy-1. The PAX-8 PPARy-1 fusion oncogene has been shown to have a dominant negative effect on thiazolidinedione-induced transactivation by PPARy (Kroll et al., 2000) and overexpression of wild-type PPARy-1 in thyroid carcinoma cell lines inhibits cell growth, an effect that is further enhanced by PPARy agonist (Martelli et al., 2002). The frequency of rearrangement in FTC is around 30% and is not found in classic PTC (Dwight et al., 2003; Reddi et al., 2007). However recently, this rearrangement has also been described in the follicular variant of PTC (Castro et al., 2006). Again, PAX-8 PPARy-1 fusion and RAS gene activation rarely occur in the same tumor (Nikiforova et al., 2003).

As mentioned above, the intranuclear receptors for vitamin A have been the target for redifferentiation therapy aiming at re-establishing uptake of radioiodine into tumor cells. In recent years, six separate isotypes of retinoic receptors, three retinoic acid receptors (RAR) and three retinoid X receptors (RXR) have been identified (Rochaix et al., 1998), but their expression pattern in thyroid carcinoma is described inconsistently (Haugen et al., 2004; Takiyama et al., 2004). Recently, a study demonstrated a beneficial effect of targeting RXR in mice implanted with a cell line derived from an anaplastic thyroid carcinoma (Klopper et al., 2008). RXR is of interest, because PPARy acts via formation of a heterodimer with RXR. This heterodimer complex interacts with peroxisome proliferator response elements and regulates the expression of target genes (Gelman et al., 1999; Vamecq & Latruffe, 1999; Murphy & Holder, 2000). Some studies suggest that the combination of thiazolidinedione and RXR selective retinoids may redifferentiate tumors by a synergistic or additive mechanism (Tontonoz et al., 1997; Mehta et al., 2000; Klopper et al., 2004).

Another potential intranuclear target in thyroid carcinoma is histone acetylation-deacetylation, which is the best understood of the post-translational modifications of the core histones (Fig. 1). It occurs by the opposing action of histone acetylases (HATs) and histone deacetylases (HDACs) (Grunstein, 1997; Strahl & Allis, 2000; Thiaga- lingam et al., 2003). Altogether, 18 HDAC enzymes have been

identified in humans and divided into three subclasses (Grozinger & Schreiber, 2002). Several studies showed that histone modifications, particularly acetylation/deacetylation, also play a role in the regula- tion of thyroid-specific and non-thyroid-specific genes in thyroid tumorigenesis. One study demonstrated that HDAC inhibitors could enhance apoptosis and cell cycle arrest in ATC cell lines (Greenberg et al., 2001). This effect most likely is mediated through an increased p53 transcriptional activity (Imanishi et al., 2002; Kitazono et al., 2002). Other observed mechanisms include the modulation of cell cycle-related molecules, such as the p27 protein (Mitsiades et al., 2005). By inhibiting HDAC in thyroid carcinoma cell lines a redifferentiating effect was observed: the expression of sodium- iodide-symporter and thyroglobulin was increased along with a gain in iodine uptake (Kitazono et al., 2001; Fortunati et al., 2004; Furuya et al., 2004; Provenzano et al., 2007).

Signaling mediated through activation of nuclear factor-KB (NF-KB) is another possible cytosolic target (Fig. 1). Cell adhesion molecules such as ICAM-1, E-selectin and VCAM-1, are regulated by NF-KB and are involved in the development of tumor metastasis and angiogenesis (King et al., 1996). During metastasis, these molecules direct the adhesion and extravasation of tumor cells from the vasculature to distant sites. Additionally, NF-KB is required by many cell types to maintain cell viability (King et al., 1996). In FTC, but not PTC, expression of the valosin-containing protein (VCP), which is involved in regulating the activation of NF-KB, correlated with disease recurrence (Yamamoto et al., 2005). NF-KB itself has also been implicated in the pathophysiology of undifferentiated and anaplastic thyroid carcino- mas (Pacifico et al., 2004). The activation of NF-KB is regulated by proteasome-mediated degradation of the inhibitor protein I K B alpha- associated protein kinase (IKBa). IKBa in turn is a target for the proteasome inhibitors, which constitute a novel class of antitumor agents.

An enzyme recently targeted for cancer prevention and treatment is cyclooxygenase (COX)-2. COX-2 is overexpressed in many cancers including thyroid carcinoma (Cornetta et al., 2002; Specht et al., 2002; Casey et al., 2004) promoting tumor development and progression. Moreover, in vitro studies showed that expression of either RET/PTC1 or RET/PTC3 in rat PCCL3 thyroid cells led to increased COX-2 mRNA levels (Puxeddu et al., 2003). Hence, COX-2 is also a potential target in the treatment of thyroid carcinoma.

In addition to the genetic causes of thyroid carcinoma, over- expression and activation of a variety of tyrosine kinase receptors and expression of angiogenic factors and their receptors play an important role in thyroid carcinoma progression. VEGF appears to be the most prominent growth factor involved in tumor angiogenesis and presumably in tumor growth and hematogenous spread of tumor cells. VEGF-R overexpression has been found in thyroid carcinoma (Soh et al., 1997; Fellmer et al., 1999) and VEGF immunoreactive protein is correlated with papillary lymph node metastases (Yu et al., 2005). Serum VEGF is significantly elevated in PTC patients compared with the control group (Pasieka et al., 2003; Klubo-Gwiezdzinska et al., 2007), especially in patients with metastatic DTC but not in those with poorly differentiated thyroid carcinoma metastases (Tuttle et al., 2002).

Epidermal growth factor receptor (EGFR) is a member of the Erb family of receptors which is abnormally activated in many epithelial tumors. Four structurally related receptors are part of this family: ErbB1 (Her1 or EGFR), ErbB2 (Her2/neu), ErbB3 (Her3) and ErbB4 (Her4). After binding to a ligand, the activation of EGFR tyrosine kinase triggers pathways that lead to cell cycle progression and apoptosis. The major downstream signaling route of EGFR family is the RAS-RAF-MAPK cascade. Increased expression of EGFR and ErbB3 has been found in DTC in comparison to benign thyroid lesions (Wiseman et al., 2008). In PTC overexpression of EGFR has been associated with a worse prognosis (Chen et al., 1999). Recently, it has been shown that EGFR contributes to RET kinase activation (Croyle et al., 2008) and is

involved in cancer cell invasion (Yeh et al., 2006) suggesting EGFR as a reasonable therapeutic target.

Vascular endothelial-cadherin (VE-cadherin)/B-catenin/AKT sig- naling is another interesting target for antineoplastic drugs. VE- cadherin localizes exclusively at specialized cell-cell contact regions of endothelium (Dejana 1996) and is involved in various aspects of vascular biology related to angiogenesis, including endothelial cell survival, migration, contact-induced growth inhibition, vascular integrity, and, most noteworthy, endothelial cell assembly into tubular structures (Breviario et al., 1995; Caveda et al., 1996; Bach et al., 1998; Carmeliet et al., 1999; Corada et al., 1999). Agents that influence VE- cadherin function are vascular targeting agents. In contrast to the antiproliferative effects of antiangiogenic therapy, antivascular target- ing aims to cause rapid shutdown of tumor vasculature, leading to extensive secondary tumor cell death (Denekamp 1993; Chaplin et al., 1996, 1999). Increased expression of VE-cadherin and ß-catenin has been demonstrated both in ATC and DTC (Wiseman et al., 2007; Murphy et al., 2008). A derangement of the VE-cadherin/B-catenin complex has been postulated to be involved in the transformation of differentiated into ATC (Wiseman et al., 2006).

Another potential target on the cell membrane is the somatostatin receptor (SSR) that can be found on many thyroid carcinoma cell lines (Ain et al., 1997). In DTC tissue samples SSR expression was demonstrated in 94% with SSR subtype 2 being the most abundant type (Druckenthaner et al., 2007). In-vitro studies have shown that somatostatin analogs may suppress growth of human thyroid carcinoma cell lines. In-vivo somatostatin receptor status may be assessed by radionuclide imaging using 99mTc-, 111In or 68Ga-labelled somatostatin analogs. Uptake of the radiotracers has been found in 51-100% of radioiodine negative patients (Teunissen et al., 2006). Those patients may potentially benefit of a targeted therapy using nonradiolabeled or radiolabeled somatostatin analogs.

2.3. Clinical trials with “emerging therapies”

In the last 5 years several new agents have been evaluated in patients with advanced DTC or ATC and more studies are ongoing (Tables 3 and 4).

Since FTC conserves a certain degree of differentiation, one logical therapeutic approach is to redifferentiate the cells and reinduce endogenous sodium-iodine-symporter expression to allow efficient

Table 3 Published results of clinical trials using "targeted therapies" in advanced DTC and ATC.

Agents	Rationale	Number of pat	Outcome (in evaluable patients)	Reference
Motesanib	Multiple TKIª	DTC: 93	PR 14%; SD 67%	Sherman et al., 2008
Axitinib	Multiple TKIª	DTC: 45	DTC: PR: 39%; SD 53% ATC: 1 PR	Cohen et al.,
		ATC: 2		2008b
Celecoxib	Inhibition of COX-2	DTC: 32	PR 3%; SD 37%	Mrozek et al., 2006
Thalidomide	Inhibition of angiogenesis (VEGF, bFGF)	DTC: 29	PR 18%; SD 32%	Ain et al., 2007
Sorafenib	Multiple TKIª	DTC: 27 ATC: 2	DTC: PR 32%; SD 68% ATC: PD 100%	Gupta-Abramson
				et al., 2008
Gefinitinib	Inhibition of EGF	DTC: 18	DTC & ATC: PR 0%, SD	Pennell
	receptor	ATC: 5	48%	et al., 2008
Combretastatin A4	Disengagement	ATC: 18	PR 0%; SD 33%	Cooney
	of VE-cadherin/ destabilization of microtubules			et al., 2006
Vorinostat	Histone deacetylase inhibitor	DTC: 16	SD 90%	Woyach et al., 2008
90Y-DOTA- TOC	Radionuclide therapy	DTC: 7	DTC: SD 29% ATC: PD	Waldherr
	targeting SSR-2	ATC: 1		et al., 2001

In several trials also patients with MTC were enrolled (see Table 5).

a See Table 2.

Table 4 Selection of currently active clinical trials in DTC and ATC.ª

Agents	Rationale	Trial ID	Location/contact
17-AAG	Inhibition of HSP90 in advanced MTC and DTC (phase II)	NCT00118248	International Mayo Clinic
AZD6244	MEK inhibitor in non- radioiodine-responsive PTC (phase II)	NCT00810537	USA canceranswers@moffitt.org
Bortezomib	Proteasome inhibitor in non-radioiodine- responsive PTC and FTC (phase II)	NCT00104871	USA/Canada M. D. Anderson Cancer Center
Combretastatin & paclitaxel/ carboplatin	Combination of disengagement of VE- cadherin and cytostatic drugs in ATC (phase II/III)	NCT00507429	International OXIGENE
E7080	Multiple TKIP in non- radioiodine-responsive DTC and in MTC (phase II)	NCT00784303	International EISAI
FR901228	HDAC inhibitor in DTC (phase II)	NCT00098813	USA Memorial Sloan- Kettering Cancer Center
Imatinib	Multiple TKIb in ATC (phase II)	NCT00115739	USA Univ. of Michigan
Sunitinib	Multiple TKIb as adjunct to radiodine treatment in DTC (phase II)	NCT00668811	USA wci. clinicaltrials@medstar.net
Sunitinib	Multiple TKIb in DTC, ATC and MTC (phase II)	NCT00510640	France Univ. Hospital Bordeaux
Vandetanib	Multiple TKIb in DTC (phase II)	NCT00537095	International Astra Zeneca

a As of December 30, 2008.

b See Table 2.

radioiodine treatment. Due to the limited efficacy of retinoic acid (see Section 2.1), several other redifferentiating agents are currently under evaluation. Already in clinical trials is bexarotene, an orally active synthetic high-affinity RXR receptor agonist with limited affinity for RAR receptors that has already been approved for the treatment of cutaneous T-cell lymphoma. A small study was done in eight 131I negative patients (Liu et al., 2008b). After 6 weeks of pretreatment with bexarotene 7400 MBq of 131I was administered. On follow-up after six months six patients had progressive disease, two were stable. Therefore, despite promising preclinical data, bexarotene did not restore susceptibility to radioiodine treatment.

Thiazolidinediones, agonists on the PPARy 1 receptor like rosiglita- zone, have also been tested as redifferentiating agents together with radioiodine treatment. In the first small study in five 131I-negative patients rosiglitazone was able to induce radioiodine uptake into metastases in only one patient (Philips et al., 2004). In two recent studies including more patients increases in radioiodine uptake after >6 weeks of pretreatment with up to 8 mg of rosiglitazone were observed in 40 and 26% of the patients, respectively (Kebebew et al., 2006; Tepmongkol et al., 2008). However, post-therapy decreases in thyroglobulin levels were only noted in 20 and 17% of the cases, respectively.

Another intranuclear target is the histone acetylase. The orally available histone deacetylase inhibitor vorinostat was studied in 16 DTC patients. No objective responses were reported and most subjects discontinued therapy because of adverse events (Woyach et al., 2008).

More promising results were seen in trials with small-molecule inhibitors. Motesanib diphosphate is a small molecule targeting several tyrosine kinases (Table 2). In a phase I study, motesanib diphosphate demonstrated antitumor activity in patients with advanced solid malignancies, including five patients with DTC (Rosen et al., 2007). On the basis of these findings, a multicenter, open-label phase II trial was initiated, to test the efficacy of motesanib diphosphate therapy in subjects with progressive DTC (Sherman et al.,

2008). Of the 93 patients included 61% had PTC, 18% Hurthle cell carcinoma and 16% FTC. Partial response was confirmed in 14% of patients and stable disease was achieved in 67%. Stable disease was maintained for more than 24 weeks in 35% of patients.

The small molecule sorafenib is approved for the treatment for advanced renal cell carcinoma and unresectable hepatocellular carcinoma. It is a multi TKI (Table 2) that prevented cell growth in TPC1 and TT cell lines, which contain the oncogenic RET/PTC1 and C634W RET mutations (Carlomagno et al., 2006). Even more encouraging were the results of an open-label phase II study, in which partial responses were reported in 7 of 25 assessable patients and stable disease in 16 patients (Gupta-Abramson et al., 2008). The two patients with ATC progressed during the treatment. However, preclinical data suggest that sorafenib might be active also against ATC, and several phase II trials are currently ongoing.

Another multi TKI that effectively blocks effects of all the VEGF receptors at subnanomolar concentrations, along with PDGFR and c- KIT is axitinib (Table 2). In a phase I study of 36 subjects with advanced solid malignancies, one of five thyroid carcinoma subjects experienced minor tumor shrinkage (Rugo et al., 2005). A multicenter, open-label phase II study was initiated to determine the efficacy of axitinib in advanced or metastatic thyroid carcinoma (Cohen et al., 2008b). Of the 60 subjects enrolled, 48% had PTC, 25% had FTC (including Hurthle cell variants), and 18% had MTC. After a median follow-up of 16.6 months disease progression was only seen in 2 of 22 assessable patients with PTC and one of 13 patients with FTC. Partial response was reported in 36% of the patients with PTC and 43% of the patients with FTC. Of the two patients with ATC one patient progressed whereas the other showed a partial response.

The small molecule inhibitor of EGFR, gefitinib, was initially introduced for therapy of non-small cell lung carcinoma. Subsequent studies suggested that the drug is only effective in the presence of a mutant EGFR and has no clinical activity in the presence of the wild type receptor (Lynch et al., 2004). Because many PTC and ATC display activated EGFR signaling, and inhibitors have had demonstrated efficacy in preclinical models, an open-label phase II study was initiated, examining the effectiveness of gefitinib in a mixed cohort of thyroid carcinoma patients (Pennell et al., 2008). Of 27 enrolled subjects, 41% had papillary, 22% follicular, 19% anaplastic and 15% had medullary thyroid carcinoma (Table 3). No formal complete or partial responses were observed in the 25 evaluable subjects, but eight patients experienced minor tumor response. One subject with ATC had stable disease beyond 12 months of therapy, similar to a case reported in a phase I trial of gefitinib and docetaxel (Fury et al., 2007).

Thalidomide is a glutamic acid derivative and was first developed as a sedative in 1954, but then worldwide usage revealed a strong teratogen potential (Franks et al., 2004). The malformations were postulated to be caused by an inhibition of vasculogenesis (D’Amato et al., 1994), setting the stage for the application as an antiangiogenic agent to treat cancer. Thalidomide is a prodrug, which requires species - and possibly tissue - specific degradation to an active metabolite (Bauer et al., 1998; Belo et al., 2001). Its precise mode of action is not completely clear, although it combines anti-inflammatory, immunomodulatory, and antiangio- genic properties. Thalidomide modulates tumor necrosis factor & (Moreira et al., 1993) and inhibits VEGF and basic fibroblast growth factor (bFGF) mediated angiogenesis (D’Amato et al., 1994). In addition, it may have direct inhibitory effects upon vascular endothelial cells (D’Amato et al., 2001; Capitosti et al., 2004). In a phase II study in 29 patients with rapidly progressive DTC 18% partial responses were observed (Table 3). In 32% of the patients stabilization of the disease was observed, whereas 50% continued to progress (Ain et al., 2007).

Combretastatin A4 phosphate (CA4P) is an antivascular and tubulin-binding agent that inhibits tumor blood flow at doses of less than 10% of the maximum tolerated dose (Dark et al., 1997); its extensive, selective and rapid inhibition of tumor blood flow which can be at least partially attributed to the inhibition of VE-cadherin/B-

catenin/AKT signaling makes it a promising novel anticancer drug (Beauregard et al., 1998). CA4P has antineoplastic activity against ATC cell lines and xenografts (Dziba et al., 2002). In a phase I trial, CA4P induced remission of ATC for 30 months in one patient (Dowlati et al., 2002). A phase II trial showed that about 25% of ATC patients treated with CA4P as single-agent had a more than 3 month progression-free survival (Cooney et al., 2006). Currently a study is evaluating the effect of combretastatin A4 in combination with paclitaxel/carboplatin in patients with ATC (Table 4).

The treatment with the somatostatin analogs like octreotide and lanreotide is widely used to ameliorate the symptoms in patients with carcinoid syndrome and has been attributed a cytostatic effect on tumor growth in this tumor entity. A study conducted in somatostatin receptor positive, progressive DTC (n=5) and ATC (n=3) showed progressive disease in all subjects under treatment with octreotide (Kohlfuerst et al., 2006). An alternative means to target somatostatin receptors is treatment with radiolabeled somatostatin analogs. These drugs are well established in the therapy of neuroendocrine tumors (Kaltsas et al., 2005). In a study which involved 20 patients with progressive thyroid carcinoma (12 MTC, 7 DTC, 1 ATC) stable disease was noted in 29% of the DTC subjects, progressive disease was found in the patient with ATC after treatment with 9ºY-DOTATOC (Waldherr et al., 2001). Of note, in several patients only faint somatostatin receptor expression was visualized by scintigraphy. All of the patients with strong receptor expression achieved a temporary stabilization of the disease, along with 25% of the patients with medium receptor expression. As a conclusion radionuclide therapy can be an option for patients with progressive disease and strong somatostatin receptor expression especially considering the fact that the therapy is usually well tolerated.

Vandetanib was one of the first described multi TKI with inhibitory effect on RET/PTC3 mutations in vitro (Carlomagno et al., 2002a). On the basis these preclinical data, a European multicenter, open-label phase II trial in patients with metastatic PTC and FTC is currently recruiting patients (Table 4).

The multi TKI sunitinib (Table 2) is approved for the treatment of renal cell carcinoma and gastrointestinal stromal tumors. No preclinical data on the effect of the drug on thyroid cancer cell lines has been published. In a phase I study, sustained clinical responses over more than four years were observed in the two treated patients with PTC and FTC, respectively (Dawson et al., 2008). Preliminary results from an open-label phase II trial in patients with progressive MTC or DTC state partial responses in 13% of 31 DTC patients, and stabilization of the disease in further 68% (Cohen et al., 2008a). In a second open-label phase II trial partial response or stable disease for more than 12 weeks was seen in 2 of 12 DTC patients (Ravaud et al., 2008). Two ongoing phase II trials are currently evaluating the efficacy of sunitinib in a larger patient population with thyroid carcinoma (Table 4).

E7080 is also an inhibitor of multiple TK, especially VEGFRs, c-KIT, PDGFR beta and stem cell factor receptor (Table 2). In animal studies it has been shown to have potent antitumor activity against small cell lung cancer and breast cancer most likely though inhibition of VEGFR-2 and - 3 (Matsui et al., 2008a, 2008b). A phase II, multicenter trial has been set up to evaluate the safety and efficacy of oral E7080 in medullary and 131I refractory, unresectable differentiated thyroid carcinomas (Table 4).

As discussed above the mechanism of action of the proteasome inhibitor bortezomib is complex but appears to include the inhibition of IKBa degradation, which leads to inactivation of NFKB. The drug has been shown to have an effect on the growth in ATC cell lines alone and in combination with other drugs (Mitsiades et al., 2006; Conticello et al., 2007). The efficacy of bortezomib treatment is currently being studied in treating patients with metastatic thyroid carcinoma not responding to radioactive iodine therapy (Table 4).

In conclusion, significant progress has been made in treatment of advanced DTC. In the light of the available data TKIs targeting

VEGF receptors and RET seem to be the most promising drugs. However, many DTC progress slowly and the decision to treat a patient has to be weighed against potential side effects of these drugs. Due to the limited side effects radionuclide therapy targeting the somatostatin receptors might be an option in DTC expressing these receptors.

3. Medullary thyroid carcinoma

The annual incidence of medullary thyroid carcinoma (MTC) is approximately 5 per million population and accounts for 3-8% of all cases of thyroid carcinoma (Ball, 2007; Schlumberger et al., 2008). Different from PTC its incidence has remained stable during the last decades (Davies & Welch, 2006). MTC arises from the parafollicular C- cells leading to hypersecretion of calcitonin and also to increased carcinoembryonic antigen (CEA) serum levels. Accordingly, serum calcitonin is a sensitive tumor marker and corresponds to tumor burden. MTC frequently metastasizes to regional lymph nodes and half of the patients may have lymph node metastasis at presentation (Boikos & Stratakis, 2008). At diagnosis, distant metastases may be present in 7-23% of patients most often affecting lungs, bones, and liver (Schlumberger et al., 2008). After surgery, the ten-year overall survival rate of unselected patients is close to 70% (Bergholm et al., 1997), but decreases rapidly in patients with distant metastases, in whom survival rates of 25% at 5 years and 10% at 10 years have been reported (Modigliani et al., 1998; Schlumberger et al., 2008).

About 25% of MTCs are hereditary occurring with either multiple endocrine neoplasia (MEN) type 2A (60%), MEN type 2B (5%), or familial medullary thyroid carcinoma (FMTC, 35%) (Brandi et al., 2001). All these closely related inherited autosomal-dominant cancer syndromes are caused by germline point mutations in the RET protooncogene. MEN 2A patients are affected by MTC, pheochromo- cytoma, and parathyroid hyperplasia. In MEN 2B, patients also develop intestinal ganglioneuromatosis, thickening of corneal nerves, and marfanoid habitus without hyperparathyroidism, whereas MTC is the only manifestation of FMTC patients (Eng, 1998; Brandi et al., 2001; Machens et al., 2005; Machens & Dralle, 2006). The close linkage of germline RET protooncogene mutations with hereditary MTC has made these disorders paradigmatic examples of molecular oncogenesis.

3.1. Current treatment standards

Prophylactic surgery is of key importance in hereditary MTC, as metastasized MTC is the most common cause of death in MEN and FMTC. The aggressiveness of hereditary MTC guides the timing of thyroidectomy (Brandi et al., 2001; de Groot et al., 2006a). As carriers of MEN 2B are at highest risk, thyroidectomy should be performed within the first year of life whereas MEN 2A/FMTC patients with mutations in codons 609, 611, 618, 620, 630, 634, and 918 should undergo thyroidectomy before the age of 5 years (for details see also Sakorafas et al., 2008). Expert surgeons are required to keep the risk of permanent hypoparathyroidism and recurrent laryngeal nerve dys- function as low as possible.

Surgery is also the treatment of choice for clinically diagnosed hereditary or sporadic MTC. Total thyroidectomy with dissection of ipsilateral and central neck compartments is recommended. In some centers, also contralateral dissection is performed (Dralle et al., 1994; Moley et al., 1997; Schlumberger et al., 2008), but no randomized trials have compared different surgical approaches (You & Wells, 2007). Successful removal of all neoplastic tissue is reflected by undetectable basal calcitonin concentrations after surgery. In contrast, postoperatively detectable serum calcitonin levels indicate persistent disease with eventual clinical recurrence. Careful imaging may reveal remnant or recurrent neoplastic tissue mostly in the neck region or in the mediastinum which may be removed by reoperation. However,

biochemical cure is only achieved in a minority of patients with MTC undergoing reoperation for recurrence (Giraudet et al., 2007). External radiation covering the neck and mediastinal region in case of evidence of persistent disease may decrease the risk of recurrence (Brierley et al., 1996; Schwartz et al., 2008). However, its effect on patient survival remains uncertain.

In patients with metastatic disease no longer amenable to surgery, treatment is largely focused on symptomatic relief (e.g. loperamide for debilitating diarrhea). Additional treatment options include chemoembolization (Fromigue et al., 2006; Bourlet et al., 2007) and external radiation plus bisphosphonate treatment for bone metastases (Kebebew & Clark, 2000). Cytotoxic chemotherapy for metastatic MTC has been largely disappointing. Treatment with doxorubicin, either alone or in combination with cisplatin, led to low rates of partial tumor response which were generally short-lived (Shimaoka et al., 1985; Schlumberger et al., 2008). Similar results were observed with an alternating combination of doxorubicin-streptozocin and 5- fluorouracil-dacarbacine (Nocera et al., 2000). Also a combination of cyclophosphamide, vincristine and dacarbacine showed limited efficacy (Wu et al., 1994).

3.2. Molecular targets in medullary thyroid carcinoma

The key role of RET in hereditary MTC has generated considerable interest in the mechanisms of action of oncogenic RET for molecular tumorigenesis (Donis-Keller et al., 1993; Mulligan et al., 1993; Santoro et al., 1995). RET encodes a transmembrane receptor of the tyrosine kinase (TK) family of proteins. The RET protein has three domains, an extracellular portion containing four cadherin-like repeats, a calcium- binding site, and a cysteine-rich region, a hydrophobic transmem- brane domain, and a cytoplasmic intracellular portion containing a typical TK domain split by an insertion of 27 amino acids (de Groot et al., 2006a; Castellone et al., 2008). The two major isoforms, RET 9 (Fig. 2) and RET 51, are highly conserved in a wide variety of species. The RET protein is the signaling receptor of a multi-molecular complex that binds growth factors of the glial cell line-derived neurotrophic factor (GDNF) family (Arighi et al., 2005). GDNF-family ligands bind RET in conjunction with glycosylphosphatidylinositol- anchored co-receptors designated GDNF family receptor & 1-4 (GFR&1-4) (Manie et al., 2001; Airaksinen & Saarma, 2002; Santoro et al., 2004). The GFL-GFR& complex induces RET homodimerization, autophosphorylation and consecutively signal transduction. RET consists of 16 tyrosines in the intracellular domain with at least 12 autophosphorylation sites. It activates multiple pathways including the Ras/RAF pathway activating the MAP kinases ERK1 and ERK2, PI3 kinase with activation of AKT, Jun NH2-terminal protein kinase (JNK), p38 MAPK, ERK5, and PLC-y (Fig. 2). Activation of these pathways leads to cell survival, proliferation, differentiation and changes in cell-cell interaction (Ichihara et al., 2004; Arighi et al., 2005; Castellone et al., 2008).

Mutations in MEN 2A and FMTC typically affect cysteines in the extracellular cysteine-rich region of RET leading to covalent dimers that display constitutive kinase activity. However, FMTC can also be associated with changes in the intracellular RET kinase domain. MEN 2B patients most frequently carry the M918T-mutation in the RET kinase domain and in a small minority harbor an A883F mutation (de Groot et al., 2006a). It has been demonstrated that the M918T- mutation induces a change in substrate specificity of the RET protein leading to altered gene expression profiles compared to MEN2A expressing tumors (Santoro et al., 1995). In sporadic MTC somatic mutations of the RET protooncogen have been observed in about 50% of cases most often affecting the RET 918 domain (Eng et al., 1996; Brandi et al., 2001; Dvorakova et al., 2008).

While these observations support the view that RET is a highly promising target for the treatment of MTC, no RET mutation is present in a significant percentage of sporadic MTCs clearly indicating that

Fig. 2. Simplified structure and functions of RET-9 (modified according to de Groot et al., 2006a; Schlumberger et al., 2008). The major autophosphorylation sites are shown as black circles, with arrows to their direct targets. Tyr1062 (Y1062) is a multifunctional docking site that binds several proteins, thereby mediating the activation of numerous signaling pathways. For the sake of simplicity the extracellular part of RET has been truncated.

Y687

1

S696

RAC

JNK

STAT3

Y752

STAT3

Y928

Y981

Src

Y1015

PLCy

PI3K

AKT

Y1062

RAS

RAF

MEK

ERK

JNK

NFKB

p38 MAPK

ERK5

additional mechanisms exist for the initiation of MTC. Furthermore, it has been demonstrated that RET mutations in sporadic MTC are often heterogeneous within a single tumor suggesting that these mutations are a secondary event (Eng et al., 1996).

In animal models, mutations in p53, PTEN, cyclin-dependent kinase 4 inhibitor C (p18-INK4c) and cyclin-dependent kinase inhibitor p27 (p27Kip1) have been described (Bai et al., 2006). Recently, high-resolution array-based comparative genomic hybridi- zation was used to more precisely define novel genes associated with MTC tumorigenesis by analyzing tumor-associated copy number alterations (Ye et al., 2008). 21 or these alterations specific to sporadic MTC were identified, with loss of 11q23.3 uniquely altered in RET negative tumors. Pathway analysis found cellular growth and proliferation as the most significant overall target and cell death as the most significant pathway targeted in sporadic MTC (Ye et al., 2008). The demonstration of frequent allelic losses suggests a possible role of tumor suppressor genes as has been previously reported in knock-out mice models (Wang et al., 2007; van Veelen et al., 2008). Also of potential therapeutic importance is the observation that VEGF is over-expressed in MTC. Loss of heterozygosity in the von Hippel- Lindau (VHL) tumor suppressor gene has been described in hereditary MTC, possibly contributing to VEGF over-expression (Koch et al., 2006). Moreover, inhibition of RET signal transduction leads to downregulation of VEGF suggesting a close relationship between RET activation and angiogenesis (Petrangolini et al., 2006).

Based on the above-described molecular pathology of MTC, inhibition of RET TK has become the primary focus for new treatment strategy for MTC. Several small molecules have been demonstrated to act as RET inhibitors in vitro mostly by competing with ATP. Two pyrazolopyrimidines (PP1 and PP2) exerted potent inhibition in the nanomolar range and were shown to block RET’s oncogenic effects in cell culture (Carlomagno et al., 2002b; Carlomagno et al., 2003). In addition, the indolocarbazole derivatives

CEP-701 and CEP-751 blocked RET MEN 2A proteins in vitro at nanomolar concentrations and also inhibited growth of tumor xenografts (Strock et al., 2003). Vandetanib, an inhibitor of VEGF- R2 TK activity (Table 2) already in clinical development was shown to efficiently block oncogenic RET kinases suggesting that targeting RET oncogenes with vandetanib might be a viable treatment strategy for MTCs with oncogenic RET mutation (Carlomagno et al., 2002b). Of note, vandetanib has also potent antiangiogenetic activity suggesting that its use may be effective against both cancer cells and tumor endothelial cells. Intriguingly, two naturally occurring mutations of valine 804 of RET caused resistance to pyrazolo- pyrimidines and 4-anilinoquinazolines suggesting that RET mutation status may be of major importance for selecting drugs for future treatment of MTC (Carlomagno et al., 2004). Moreover, this observation may point to a potential mechanism of acquired drug resistance. More recently, it was shown that the RET Y806C mutation also induced RET kinase resistance to vandetanib (Carlomagno et al., 2008). This mutation is a natural RET mutation identified in a patient affected by MEN 2B. Again, it may be envisaged that mutations at this site can mediate secondary resistance formation in patients treated with vandetanib. Similarly, sorafenib, a bi-urea with potent inhibition of certain proangiogenic receptor TK (Table 2) was also shown to potently inhibit oncogenic RET mutants including the growth of cells carrying RET V804L and RET V804M mutants that were found resistant to anilinoquinazolines and pyrazolopyrimi- dines. After 3 weeks of oral treatment, the volume of MTC cell xenografts was strongly reduced whereas in vehicle-treated mice it rapidly increased. This inhibition of tumor growth was paralleled by a decrease in RET phosphorylation (Carlomagno et al., 2006).

Besides directly addressing oncogenic RET as a drug target, RET stimulated intracellular signaling may hold promise as therapeutic target in MTC. In particular, RAS-RAF-ERK, NFKB, and PI3K-AKT pathways may become a relevant target.

3.3. Clinical trials with “emerging therapies”

Elucidation of the molecular pathology of MTC with oncogenic RET as a critical driver of neoplastic transformation and promising pre- clinical data using TKI has recently led to a rapidly growing number of clinical trials including phase III trials comparing TK inhibitors with placebo (Tables 5 and 6). So far, most trials are still recruiting or results have only been published as abstracts.

Beside its established blockade of BCR-ABL in chronic myelogenous leukemia and c-KIT in gastrointestinal stromal tumors in vitro experiments have shown that imatinib mesylate (STI 571) inhibits RET autophosphorylation in MTC cells harboring MEN-associated oncogenic RET mutations. However, high concentrations of imatinib are needed for effective RET inhibition (de Groot et al., 2006b). In three open label phase II trials including a total of 30 subjects with advanced MTC, imatinib mesylate was well tolerated but no objective tumor response was observed. Transient stable disease was achieved in 36% of patients (Gross et al., 2006; de Groot et al., 2007; Frank-Raue et al., 2007). Similarly, no objective tumor response was observed with a combination of imatinib, dacarbazine and capecetabine in seven patients with advanced MTC (Hoff et al., 2006).

Published results are also available for axitinib (AG-013736), a small molecule TKI not targeting RET but effectively blocking VGFR, PDGFR, and c-KIT in low nanomolar concentrations (Table 2). In an open label phase II trial, partial responses were found in 22% of patients with advanced or metastatic thyroid carcinoma including eleven subjects with MTC (Cohen et al., 2008b). In 2 out of 5 evaluable patients with MTC a partial response was noted and none had progressive disease. These data suggest that patients with MTC may respond to angiostatic treatment even when RET is not specifically targeted.

For all other drugs only preliminary results published as abstracts are available. XL184 targets several TK (Table 2) including RET and MET. It strongly inhibits cell proliferation in MTC cells harboring oncogenic RET and showed substantial inhibition of RET and MET phosphorylation in an MTC xenograft tumor model (Salgia et al., 2008). In a phase I study of XL184 all but one of 17 evaluable patients with MTC showed a decrease in serum calcitonin of at least 50% and all patients had either stable disease or confirmed partial response (Fig. 3). As these results are highly promising, a phase III efficacy study of XL184 is currently recruiting adults with MTC (Table 6).

Table 5 Results of clinical trials using "targeted therapies" in MTC.

Agents	Rationale	n	Outcome (in evaluable patients)	Reference
Motesanib	Multiple TKIª	83	PR 2%; SD 47%	Schlumberger et al., 2007
Vandetanib	Multiple TKIª	49	PR 14%; SD 43%	Wells et al., 2007; Haddad et al., 2008
Imatinib	Inhibition of C-KIT and PDGF	30	SD 36%	Gross et al., 2006; de Groot et al., 2007; Frank-Raue et al., 2007
XL184	Multiple TKI (incl. RET)ª	22	PR 53%, SD 47%	Salgia et al., 2008
90Y-DOTA-	Radionuclide	12	SD: 42%	Waldherr et al., 2001
TOC	therapy
	targeting SSR-2
Axitinib	Multiple TKIª	11	PR 40%; SD 60%	Cohen et al., 2008b
Sunitinib	Multiple TKIª	7	PR 14%, SD 71%	Cohen et al., 2008a; Kelleher & McDermott, 2008
Thalidomide	Inhibition of angiogenesis	7	PR 18%; SD 18%	Ain et al., 2007
Sorafenib	Multiple TKIª	6	CR 17%; PR 33%	Kober et al., 2007; Gupta- Abramson et al., 2008
Gefinitinib	Inhibition of	4	PD 100%	Pennell et al., 2008
	EGF receptor

n number of patients.

a See Table 2.

Table 6 Selection of currently active clinical trials in MTC.ª

Agents	Rationale	Trial ID/trial acronym	Location/contact
Imatinib & dacarbazine	Multiple TKIb (phase I/II)	NCT00354523	USA M.D. Anderson Cancer Center
Radioimmunotherapy	Anti CEAxanti-DTPA antibodies di-DTPA-1311	NCT00467506	France Nantes University Hospital
Sorafenib	Multiple TKIb (phase II)	NCT00390325	USA National Cancer Institute
Sorafenib	Multiple TKIb (phase II)	NCT00654238	USA University of Pennsylvania
Sunitinib	Multiple TKIb (phase II)	NCT00381641	USA University of Chicago
Vandetanib	Multiple TKIb in MTC (phase I/II in children)	NCT00514046	USA National Cancer Institute
Vandetanib	Multiple TKIb in MTC (phase II)	NCT00410761	International Astra Zeneca
XL184	Multiple TKIb in MTC (phase III)	NCT00704730	International Exelixis

a As of December 30, 2008.

b See Table 2.

The multiple TKI motesanib diphosphate (Table 2) was studied in 83 subjects with symptomatic or progressive MTC. 51% of patients experienced stable disease and 2% had a confirmed partial response. Intriguingly, maximum plasma concentrations of motesanib dipho- sphate were lower than expected, possibly due to impaired resorption in MTC patients frequently suffering from profound diarrhea (Schlumberger et al., 2007, 2008; Sherman et al., 2008). Thus, higher doses of motesanib diphosphate may be required in MTC for optimum treatment response.

The effectivity of the multiple TKI sorafenib was studied in five patients with symptomatic and metastasized MTC. One complete and one partial response were observed after six months of treatment (Kober et al., 2007). Currently, several trials are evaluating the activity of sorafenib in treating patients with metastatic, locally advanced or recurrent MTC, either alone or in combination with bevacizumab (Table 6). Similarly, a phase I study combining sorafenib and the farnesyltransferase inhibitor tipifarnib has been initiated and a partial response has been reported in a patient with advanced MTC (Sher- man, 2008).

The multiple TKI sunitinib inhibits RET autophoshorylation with an IC of approximately 100 nmol/l in cultured TT cells (human MTC cell line with an active RET mutation) indicating that MTC might be an

Fig. 3. Best tumor response to XL184 in 17 patients with MTC. Maximum percent change from baseline in the sum of the longest diameters (SLD) of target lesion for each patient. * modified according slides of the presentation by Ravi Salgia at the ASCO meeting 2008 Abstract No: 3521 (slides available under: http://www.asco.org/ASCO/Abstracts+%26+ Virtual+Meeting).

0

Maximum change from baseline in sum of target lesions

-10

-20

-30

-40

-50

appropriate target for disease-directed studies (Chow & Eckhardt, 2007).This view was supported by a dramatic clinical response to sunitinib in a patient with metastatic MTC (Kelleher & McDermott, 2008). In a phase II study using sunitinib in refractory carcinomas six patients with MTC were included. Stable disease was found in 83% and progressive disease in 17% of patients (Cohen et al., 2008a). In two other phase II trials altogether 18 with MTC have been studied. However, these preliminary reports did not differentiate between MTC and other forms of thyroid carcinoma (Goulart et al., 2008; Ravaud et al., 2008). Several trials with sunitinib in MTC are currently running (Table 10).

Vandetanib is a TKI (Table 2) that has been proposed early as a potential treatment of MTC based on its activity in vitro and in MTC xenograft models (Carlomagno et al., 2002a). On the basis that vandetanib blocks most oncogenic RET mutations, open label phase II trials were initiated to investigate the efficacy of vandetanib in metastatic familial MTC. In a first trial, 30 patients with locally advanced or metastatic hereditary MTC received treatment with vandetanib (initial dose 300 mg/day). Confirmed partial response was observed in 5/30 patients and additional 15/30 patients experienced stable disease >24 weeks (Wells et al., 2007). In a second trial, patients with unresectable locally advanced or metastatic hereditary MTC received vandetanib in a dose of 100 mg. Of 19 patients, 15 had a confirmed RET germline mutation whereas the mutation status of the other four patients was unknown. Preliminary objective tumor assessments have demonstrated partial responses in two patients, stable disease >24 weeks in six patients, and progressive disease in two patients (Haddad et al., 2008). These still preliminary results indicate that vandetanib has significant activity in patients with MTC. In addition, calcitonin levels dropped by more than 50% in most subjects. Based on these promising results, an efficacy study comparing vandetanib to placebo in MTC is currently ongoing. However, it is important to bear in mind that inhibition of tumor growth and blockade of calcitonin gene expression may involve different pathways of RET signaling (Akeno-Stuart et al., 2007). Thus, in patients treated with TKI like vandetanib or XL184, circulating calcitonin may no longer reflect tumor burden.

Gefitinib is a small molecule inhibitor of the EGF receptor which has been used in an open label phase II trial in patients with different kinds of thyroid carcinoma including four patients with MTC. No complete or partial responses were observed and medium progres- sion free survival was < 3 months in patients with MTC (Pennell et al., 2008).

A variety of treatment strategies not directly targeting RET or other TKs have been tested in MTC in vitro or are currently studied in clinical trials. The proteasome inhibitor bortezomib, which is successfully used in multiple myeloma, was found to induce apoptosis in MTC cells probably related to inhibition of NFKB (Mitsiades et al., 2006). Thalidomide was studied in an open-label nonrandomized phase II trial in advanced thyroid carcinomas also including seven patients with MTC. One of five evaluable patients had a partial response and one patient experienced stable disease (Ain et al., 2007).

Radionuclide therapy targeting specifically MTC cells has also been suggested to be superior to cytotoxic chemotherapy (Chatal et al., 2006). Although initial reports on treatment with 131I-MIBG were encouraging, further studies could not confirm significant benefits with this treatment modality (Clarke 1991; Troncone & Rufini, 1997; Pasieka et al., 2004). Somatostatin receptors 1-5 are variably expressed in MTC cells (Mato et al., 1998) and selective activation of receptor subtypes differentially affects calcitonin secretion and viability in vitro (Zatelli et al., 2006). The radiolabeled somatostatin analog 90Y-DOTATOC was introduced for treatment of advanced MTC and led to SD in 42% of cases (Waldherr et al., 2001). More recently 90Y-DOTATOC was investigated in a phase II trial in 31 patients with metastasized MTC (Iten et al., 2007). A response with decreasing serum calcitonin was observed in 29% of patients and was associated

with longer survival (p=0.02). Intriguingly, scintigraphic tumor uptake was not associated with treatment response. Pretargeted anti-CEA radioimmunotherapy using bispecific antibodies directed against both CEA and diethylenetriamine penta-acetic acid (DTPA) followed by a 131I-labeled bivalent hapten was studied in 29 patients with advanced progressive MTC (Chatal et al., 2006). Compared to untreated MTC patients with comparable prognostic indicators overall survival was significantly longer after radioimmunotherapy (110 vs. 61 months, p<0.03). This concept is currently studied in MTC in a phase II trial.

Aberrant histone deacetylase (HADC) activity is seen in a variety of malignancies and HADC inhibitors like vorinostat have been shown to induce cell death and sensitize cells to cytotoxic chemotherapy in patients with advanced carcinoma (Mitsiades et al., 2005). In a phase II study in 19 patients with advanced thyroid carcinoma including 3 patients with MTC vorinostat was given in a dose of 200 mg twice daily. However, no complete or partial response was observed and it was concluded that vorinostat is not effective in thyroid carcinoma (Woyach et al., 2008).

Currently, 17-AAG (17-allylamino-17-demethoxygeldanamycin) is studied in patients with inoperable or metastatic thyroid carcinoma including MTC. 17-AAG induces inhibition of heat shock protein 90 (HSP90), a molecular chaperone needed for optimum activity of oncogenic protein kinases. It has been demonstrated in vitro that inhibition of HSP90 alters the biology of thyroid cells with rearranged RET (Marsee et al., 2004).

In addition, immunotherapy with dendritic cells has been success- fully evaluated in a transgenic mouse model for MTC (Papewalis et al., 2008) and this approach has occasionally been tested in humans. However, a robust effect has not been demonstrated yet (Schott et al., 2001; Schott et al., 2002).

In conclusion, targeting RET seems to hold great potential in the treatment of MTC harboring oncogenic RET mutations. In addition, inhibition of VEGF (e.g. by axitinib) may lead to significant inhibition of tumor progression. The available results clearly indicate that these new compounds will soon replace cytotoxic drugs in the treatment of advanced MTC.

4. Parathyroid carcinoma

Parathyroid carcinoma is a rare but often devastating cause of primary hyperparathyroidism (Shane, 2001). Patients typically pre- sent with symptomatic hypercalcemia and occasionally with palpable neck mass or recurrent laryngeal nerve palsy as a sign of locally advanced disease. Lung, liver and bone are the primary site for distant metastasis. If metastasized, parathyroid carcinoma can cause relent- less hypercalcemia and metabolic complications that are exceedingly difficult to control. Rarely, patients die because of direct effects of tumor invasion, but most likely succumb to intractable hypercalcemia. Therefore, improving treatment of hypercalcemia is one of the most important issues for patients with advanced parathyroid carcinoma. Definitive diagnosis of parathyroid carcinoma requires the presence of invasion of surrounding structures, local recurrence or metastasis, i.e. a stage, at which cure usually is impossible. Elevated levels of hyperglycosylated hCG in plasma or urine may help to identify a carcinoma preoperatively (Rubin et al., 2008). Histopathologic features of parathyroid carcinoma and adenomas overlap making a certain diagnosis often impossible.

4.1. Current treatment options

Early en bloc resection at the time of initial surgical intervention is the only curative treatment (Shane 2001; Shattuck et al., 2003; Rodgers & Perrier, 2006). Tumor spillage and incomplete resection results in early and incurable recurrence. Thus, the first surgical intervention is a critical step in the course of the disease. To control

hypercalcemia in advanced stages, repeated surgical reduction of tumor burden or resection of metastasis is an option. External beam radiation as primary therapy for unresectable tumors or to shrink tumor size preoperatively has not been successful. However, post- operative radiation therapy was able to lower the risk for disease recurrence (Wynne et al., 1992; Busaidy et al., 2004).

No phase II trial investigating cytotoxic chemotherapy has been performed. One patient was successfully treated with a combination of cyclophosphamide, 5-fluorouracil and dacarbacine (Bukowski et al., 1984). The partial biochemical response lasted more than 5 months. In another case, treatment with darcabacine alone (Calandra et al., 1984) decreased PTH and serum calcium levels after one course of treatment. Not surprisingly, chemotherapy does not provide a curative strategy. However, the overall negative appraisal of chemotherapy (Hakaim & Esselstyn, 1993; Shane, 2001; Busaidy et al., 2004; Rodgers & Perrier, 2006) has to be judged with caution. Also a modest response for a foreseeable period of time may offer important palliation.

To control hypercalcemia, rehydration with intravenous saline and loop diuretics to enhance renal calcium excretion are standard treatments. Bisphosphonates are effective, but loose efficacy over time. Acutely, steroids and calcitonin can be given, but effects last no longer than a couple of days (Shane 2001). Amifostine (WR-2721) is a hypocalcemic agent that decreased serum calcium by inhibiting PTH secretion (Glover et al., 1985). Severe toxicities limit its use. In one case report, octreotide has induced a modest reduction of PTH serum levels (Koyano et al., 1994). One recent report describes radio- frequency ablation and transcatheter arterial embolization in a patient with hormonally active liver metastasis (Artinyan et al., 2008). Good control of hypercalcemia for a period of 4 months was reported.

4.2. Molecular targets in parathyroid carcinoma

The recently described mutations in the HRPT2 gene and the transcriptional loss of its gene product, parafibromin, seem to be specific for parathyroid carcinoma, and may facilitate diagnosis and point to a potential therapeutic target. HRPT2 has been identified as the responsible gene for hypoparathyroidism jaw tumor syndrome (HPT-JT), which is occasionally associated with parathyroid carcino- mas. Testing parathyroid carcinomas, in 10 out of 15 cases a somatic HRPT2 mutation and in three cases a germline mutation was found (Shattuck et al., 2003). These findings were confirmed in another study showing HRPT2 mutations in 6 out of 7 carcinomas with 2 having germline mutations (Cetani et al., 2004). Furthermore, a LOH of HRPT2 in tumor tissue was found in 6 patients giving at least 5 patients with two hits on the HRPT2 locus. These mutations usually result in a premature transcriptional stop and, thus, carcinomas do not express parafibromin, which can be assessed by immunohistologic staining (Gill et al., 2006; Juhlin et al., 2007; Fernandez-Ranvier et al., 2008; Howell et al., 2009). Interestingly, parathyroid carcinomas found in patients with end stage kidney disease seem not to be associated with HRPT2 mutations (Tominaga et al., 2008). Parafibro- min is the functional homolog of Hyx (Drosophila melanogaster) and functions as a nuclear Wnt signaling component (Mosimann et al., 2006). Constitutive Wnt signaling is causally involved in many different tumor types. However, mutations and/or loss-of-heterozygosity of the HRPT2 tumor suppressor gene are expected to compromise rather than enhance pathway output. Subcellular fractionation and laser confocal microscopy of normal human parathyroid gland demonstrated expres- sion of parafibromin in both the cytoplasmic and nuclear compartments (Woodard et al., 2005). Transient over-expression of wild-type parafibromin, but not a missense mutant, inhibited cell proliferation, and blocked expression of cyclin D1, a key cell cycle regulator previously implicated in parathyroid neoplasia (Hsi et al., 1996; Woodard et al., 2005).

Cyclin D1 or PRAD1 (parathyroid adenoma 1) is an oncogene located at 11q13. A chromosomal rearrangement of the cyclin D1 gene

with the regulatory region of the PTH gene has been reported in 5% of parathyroid adenomas (Arnold et al., 1989; Arnold 1993; Mallya & Arnold, 2000). In addition, the cyclin D1 oncoprotein is overexpressed in 18-40% of parathyroid adenomas (Hsi et al., 1996; Vasef et al., 1999; Tominaga et al., 2008) and even more frequent in parathyroid carcinomas, having been identified in up to 91% of such tumors (Hsi et al., 1996; Vasef et al., 1999).

Significant telomerase activity was reported in parathyroid carcinoma cells (Falchetti et al., 1999). Typically, telomerase activity is addressed by antiviral therapy, e.g. azidothymidine (AZT). Accord- ingly, in primary cultures from 2 carcinoma patients and 3 patients with parathyroid adenomas AZT blocked telomerase activity in vitro inhibiting proliferation and inducing an apoptosis (Falchetti et al., 2005). As data investigating other malignancies also suggest a growth inhibiting effect of AZT alone or in combination with other antimetabolites (Pressacco & Erlichman, 1993), this approach may become also clinically interesting.

4.3. Clinical experience with “emerging therapies”

The effect of cinacalcet, a calcimimetic agent that increases the sensitivity of the calcium-sensing receptor, to control hypercalcemia in patients with inoperable parathyroid carcinoma was studied in a multicenter, open-label, single-arm, dose-titration trial. 29 patients were included receiving cumulative doses of up to 360 mg/day cinacalcet. The primary endpoint was the proportion of patients experiencing at least a 0.25 mmol/l (1 mg/dl) reduction in serum calcium at the end of the titration phase. A calcium reduction was apparent in 62% of patients with a decline in mean serum calcium from 3.5±0.1 mmol/l to 3.1± 0.1 mmol/l. The average reduction was 0.42 mmol/l. The greatest reduction was seen in patients with the highest serum calcium levels. Eighteen patients remained in the study for at least 16 weeks. In these patients, the mean reduction was 0.95 mmol/l. In five patients adverse effects (i.e. nausea, vomiting) resulted in withdrawal of study medication. Seven patients died during the study or within 30 days of study withdrawal.

Two different approaches of immunotherapy have been published as case reports. In one approach a humoral response against circulating PTH was induced with good success (Bradwell & Harvey, 1999; Betea et al., 2004). Immunizing with both human and bovine 1- 34 PTH peptides combined with Freund’s complete adjuvans led to a fall in serum calcium levels followed by clinical improvement with remission of nausea and vomiting, relief of pain and mobilization of the previously bed bound patient. PTH and calcium levels remained controlled for more than 24 months, and the size of pulmonary metastases decreased by 39-71%. In another case, a CD8+ based cytotoxic T-cell response was induced after repeated vaccinations with antigen pulsed dendritic cells (Schott et al., 2000). Dendritic cells were exposed to tumor lysate or PTH and antigen loaded cells were injected into inguinal lymph nodes. However, PTH and calcium continued to rise and progressive pulmonary metastases were noted at the end of vaccination despite a clear immune response against the tumor lysate in vitro.

In conclusion, cinacalcet is an important new option in controlling hypercalcemia in patients with parathyroid carcinoma. Very pre- liminary data suggests that immunization against PTH may be used as an approach combining control of hypercalcemia and tumor progression.

5. Adrenocortical carcinoma

In contrast to the benign adrenocortical adenomas with a prevalence of >4% (Grumbach et al., 2003; Song et al., 2008) adrenocortical carcinoma (ACC) has only an estimated annual incidence of 1-2 per million population. The majority of patients with ACC present with signs and symptoms of autonomous adrenal steroid secretion (mostly

glucocorticoid and/or androgen excess), but in 20-30% of cases symptoms related to the tumor mass lead to primary diagnosis, and in 10-15% ACC is diagnosed incidentally during imaging procedure for other purposes. In about a third of patients distant metastases (most frequent in lung and liver) are already present at time of primary diagnosis.

5.1. Current treatment standards

Radical surgery is the standard therapy for patients with localized and regional ACC (stages I-III) (Schteingart et al., 2005; Allolio & Fassnacht, 2006; Libe et al., 2007). Due to a high risk of recurrence, most centers recommend adjuvant therapy even after complete resection. The best available data derive from a large retrospective multicenter study demonstrating the efficacy of mitotane - a synthetic derivative of the insecticide dichlorodiphenyltrichloroethane (DDT) - to reduce signifi- cantly the risk of recurrence and death (Terzolo et al., 2007). A small study suggested a protective effect of adjuvant tumor bed irradiation in patients with high risk for local recurrence (Fassnacht et al., 2006; Polat et al., in press). However, despite adjuvant measures the rate of recurrence after radical resection is still around 50% (Terzolo et al., 2007).

In patients with metastasized ACC, standard of treatment consists of mitotane in combination with cytotoxic drugs (Hahner & Fassnacht, 2005; Schteingart et al., 2005). Etoposide, doxorubicin, cisplatin plus mitotane or streptozotocin plus mitotane are the two most promising treatment regimens in patients not amenable to complete resection (Khan et al., 2000; Berruti et al., 2005) and are currently compared in an international phase III trial. No second or third line therapy is established. Hypersecretion of hormonal steroids in ACC frequently contributes to the disease burden and can severely affect quality of life and has to be treated adequately (Fassnacht & Allolio, in press).

Despite treatment, the overall prognosis is limited indicating the need for improved therapies. Recent data from the German ACC Registry demonstrated an overall survival of 47% after 5 years and 41% after 10 years (Fassnacht et al., 2009). However, in patients with metastases (stage IV) median survival is <15 months.

5.2. Molecular targets in adrenocortical carcinoma

The molecular pathogenesis of adrenocortical tumors is still incompletely understood (Barlaskar & Hammer, 2007; Soon et al., 2008) although recent gene expression studies have significantly increased our knowledge (Giordano et al., 2009; de Reyniès et al., 2009). Some insights come from hereditary tumor syndromes associated with the development of ACC. In the Li-Fraumeni syndrome (Li & Fraumeni, 1969) the frequency of ACC is up to 4% (Hisada et al., 1998). Seventy percent of patients with Li-Fraumeni syndrome have germline mutations of the p53 tumor suppressor gene located at the 7p13 locus (Varley et al., 1999). A second variant is caused by a heterozygous germline mutation in the hCHK2 gene (Bell et al., 1999). In children with ACC in southern Brazil, a specific germline mutation of p53 encoding an R337H amino acid substitution has been demonstrated. This mutation leads to a pH-sensitive and temperature-dependent alteration in the function of the p53 protein (DiGiammarino et al., 2002). Somatic mutations in the p53 gene have also been found in tumors of patients with sporadic ACC (Reincke et al., 1994). In recent years, extensive studies have been conducted to identify small molecules that manipulate p53, including restoration of mutant p53 conformation to wild-type, disruption of murine double minute-2 (Mdm2)-p53 binding to increase p53 level and inhibition of Mdm2 E3 ubiquitin ligase activity to prevent p53 degradation (Sun, 2006). However, none of these compounds have been tested in ACC.

Another hereditary syndrome associated with ACC is the Beckwith- Wiedemann Syndrome (BWS), a congenital overgrowth syndrome characterized by exophthalmos, macroglossia, gigantism, and the development of childhood tumors (Maher & Reik, 2000). BWS has

been mapped to the 11p15.5 region and is associated also with Wilms tumor and hepatoblastoma. Genes located at 11p15 and implicated in the pathogenesis of BWS are IGF-2, H19, and p57kip2. IGF-2 is maternally imprinted, whereas H19 and p57kip2 are both paternally imprinted. Uniparental paternal isodisomy for this locus associated with IGF-2 overexpression has been observed in BWS. In sporadic ACC rearrangement at the 11p15 locus with overexpression of IGF-2 is frequently observed caused either by duplications of the paternal 11p15 allele or by loss of the maternal allele containing the H19 gene. In fact, IGF-2 is the single most up-regulated transcript in 80-90% of ACCs (Gicquel et al., 1997, 2001; Giordano et al., 2003; de Fraipont et al., 2005). IGF-2 mainly elicits its cellular effects through the ubiquitously expressed IGF 1 receptor (IGF-1R), which is also overexpressed in most ACCs (Weber et al., 1997). These observations suggest that activation of the IGF pathway is a key mechanism employed by tumor cells during adrenocortical tumorigenesis. Accordingly, two recent publications demonstrated that inhibition of IGF-2 action by blocking IGF-1 receptor leads to reduced growth of ACC cells in vitro (Almeida et al., 2008) and in vivo models (Barlaskar et al., 2008).

In both benign and malignant adrenocortical tumors, ß-catenin accumulation has been frequently observed indicating activation of the Wnt-signaling pathway (Gaujoux et al., 2008; Tadjine et al., 2008a; Tadjine et al., 2008b). This is explained in a subset of these tumors by somatic mutations of the ß-catenin gene CTNNB1 which may contribute to tumor progression (Gaujoux et al., 2008). However, no specific drug targeting the Wnt pathway is currently clinically available.

Different from earlier expectations and in contrast to thyroid carcinomas, no activating mutations were found in the ACTH receptor in adrenal tumors (Latronico et al., 1995; Light et al., 1995). In fact, in ACC rather a loss of heterozygosity of the ACTH receptor with reduced expression of ACTH receptor mRNA was observed supporting the view that ACTH is mainly a differentiating factor for adrenocortical cells and that growth promoting activities of pro-opiomelanocortin (POMC) may reside in the N-terminus of POMC (Beuschlein et al., 2001; Fassnacht et al., 2003). Obviously these findings raise the question whether suppression of POMC (e.g. by exogenous glucocorticoids) in combination with ACTH administration may play a role in the management of patients with ACC. However, a recent in-vivo study in mice could not confirm a relevant mitogenic activity of N-terminal POMC in normal adrenal glands (Coll et al., 2006).

Chromosomal instability has been described in malignant adrenal tumors indicating defects in the mitogenic machinery (Dohna et al., 2000). Using comparative genomic hybridization analysis, a high number of changes in ACCs compared to adrenocortical adenomas (mean of 7.6-14 changes vs. 1.1-2 changes) have been demonstrated (Zhao et al., 1999; Sidhu et al., 2002). It has been shown that the number of somatic aberrations in ACC also predicts prognosis (Stephan et al., 2008). Cytotoxic drugs may further increase the number of genomic alterations, thereby promote tumor dedifferentia- tion and resistance to current treatment modalities.

VEGF is significantly elevated in tumor tissue and circulating blood in patients with ACC (de Fraipont et al., 2000; Kolomecki et al., 2001; Zacharieva et al., 2004). In addition, VEGF and its receptor VEGF-R2 is strongly expressed in the majority of ACCs (108/148 and 144/148 ACC samples; Fassnacht et al. unpublished results) suggesting that vascular-targeted therapies may hold promise for patients with ACC, although the clinical response to anti-angiogenetic treatment in other tumor entities did not closely correlate with the expression level of VEGF or its receptors.

The epidermal growth factor receptor (EGFR) is overexpressed in the vast majority of ACC samples (Kamio et al., 1990; Sasano et al., 1994; Fassnacht et al., 2007). However, EGFR expression did not correlate with clinical outcome in 133 ACC patients. In addition, no mutations of the EGFR gene have been found in ACC (Fassnacht et al., 2007). The HER-2/neu protein, target for the monoclonal antibody

trastuzumab (herceptin), was investigated in 17 ACCs, but no specific membranous immunostaining was detected (Saeger et al., 2002).

In the last few years drugs with antiproliferative activity in other tumor entities have been investigated in ACC in vitro. PPARy is highly expressed in most ACC samples and thiazolidinediones inhibited cell growth in ACC cell lines (Betz et al., 2005; Ferruzzi et al., 2005; Cantini et al., 2008). As bisphosphonates may have direct effect on tumor cell proliferation (Diel et al., 1998), the impact of bisphosphonates on ACC cell lines was investigated demonstrating that both clodronate and pamidronate lead to a dose-dependent inhibition of cell growth and P450c21 activity in adrenocortical cells (Fassnacht et al., 2002). However, the short half life of these drugs in the circulation probably precludes a relevant clinical effect unless these drugs could be tagged with a compound targeting the drug to the adrenocortical tumor cells.

It has long been appreciated that ACC is relatively resistant to standard cytotoxic chemotherapy. At the molecular level, one explanation might be the high expression of P-glycoprotein, also known as the multidrug resistance protein MDR1 (Flynn et al., 1992; Haak et al., 1993). This protein, encoded by the ABDB1 gene, functions as an ATP-dependent drug efflux pump transporting cytotoxic agents out of the cell. Currently, a trial is investigating the effects of tariquidar (XR9576), a third-generation noncompetitive inhibitor of the P- glycoprotein efflux pump (Table 8). Another reason for failure of cytotoxic drugs is the expression of DNA repair genes. For other tumors, it has been shown that expression of ERCC1 plays a key role in the resistance to platinum compounds. In a retrospective series it has been demonstrated that ACC patients with low or absent expression of ERCC1 in their tumor respond better to treatment with a platinum- based cytotoxic chemotherapy than tumors with high expression of ERCC1 (Ronchi et al., in press).

A different approach that might hold some promise is based on radiolabeled metomidate - a specific tracer for molecular imaging of cytochrome P450 family 11B (Cyp11B) enzymes. Since Cyp11B is

highly specific for the adrenal cortex, radiolabeled metomidate used as a PET or scintigraphy tracer is able to visualize the adrenal gland in animals and humans (Bergstrom et al., 1998; Hahner et al., 2008). In patients, adrenocortical tissue showed high and specific tracer uptake of radiolabeled metomidate in both primary tumor and ACC metastases, whereas non-adrenocortical tumors did not exhibit any tracer uptake (Khan et al., 2003; Minn et al., 2004; Hennings et al., 2006; Hahner et al., 2008) (Fig. 4). In contrast to the PET tracer 11C- metomidate, iodine-labeled metomidate holds also therapeutic potential as 131I-iodine may be used for specific radionuclide therapy. Preliminary experience in patients with ACC demonstrated that high therapeutic doses can be achieved in the target tissue, comparable to those deposited by other radionuclide treatment regimens for other malignancies (Hahner et al., 2009). However, this method has to be further evaluated to better estimate its clinical value in treatment of ACC.

5.3. Clinical experience with “emerging therapies”

Only recently, several clinical trials using “new drugs” have been initiated in ACC (Table 7 and 8). However, the first preliminary results of these new drugs in ACC have been largely disappointing. In a single case report significant tumor regression has been reported for the anti-angiogenic compound thalidomide (Chacon et al., 2005). A combination of the EGF receptor inhibitor erlotinib with gemcitabine exhibited only limited efficacy as salvage therapy in 10 patients with advanced ACC (Quinkler et al., 2008). Similarly, no response to the EGF receptor antagonist gefitinib was seen in 19 patients with advanced ACC (Samnotra et al., 2007). Furthermore, in 10 patients no response was found with a combination of the anti-VEGF antibody bevacicumab plus capecitabine given as salvage treatment suggesting that this combination has also no relevant activity in advanced ACC (Wort- mann et al., 2009).

Fig. 4. Imaging of adrenocortical tissue in a patient with metastasized ACC by [123I]iodo-metomidate scintigraphy. 50 year old patient with androgen producing ACC on the right side with soft tissue infiltration and arrosion of the 12th rib. Imaging with 183 MBq 123I-iodo-metomidate demonstrates uptake of the tracer in the primary tumor (thick black arrows), bone metastases (thin arrows) and the healthy left-sided adrenal gland (arrowheads). Whole body imaging (on the left side) was performed 4 h, SPECT-CT imaging (on the right side) 5 h after the injection of the radiotracer.

A

R

L

T: 4,8

S: 4,8

P: 1575,4

P

42

A

R

L

T: 4,8

S. 4,8

P: 1575,4

330s

P

42

RVL

Table 7 Results using "targeted therapies" in ACC.

Agents	Rationale	n	Outcome	Reference
Gefitinib	Inhibition of EGFR signaling	19	No	Samnotra
			response	et al., 2007
Bevacizumab +	Inhibition of VEGF signaling +	10	No	Wortmann
capecitabine	cytotoxic drug		response	et al., 2009
Erlotinib +	Inhibition of EGFR signaling +	10	1 minor	Quinkler
gemcitabine	cytotoxic drug		response	et al., 2008
Imatinib	Inhibition of c-KIT and PDGF	4	No	Gross et al., 2006
			response
Thalidomide	Anti-angiogenesis	1	Partial	Chacon et al.,
			response	2005

n number of patients.

As ACCs express high levels of IGF-2 (see Section 5.2) (Giordano et al., 2003; de Fraipont et al., 2005; Almeida et al., 2008), which act via the IGF-1 receptor, blockade of the IGF-1 receptor has been suggested as a promising treatment target in ACC. Several trials are ongoing or planned (Table 8).

Sunitinib has been found to exert adrenal toxicity in animals and the histological examination of the adrenal gland of rats and monkeys treated with sunitinib showed hemorrhage, necrosis, congestion, hypertrophy and inflammation. In various clinical trials, 12 of 400 investigated patients developed laboratory findings of adrenal insufficiency but without relevant clinical impairment. These effects might indicate some specific activity of the drug in adrenal tissue. These data in combination with the presumable important role of angiogenesis for ACC led to a phase II trial with sunitinib as monotherapy in patients failing platinum based cytotoxic therapy (Table 8).

Furthermore, a study using a combination of the multiple TKI sorafenib and metronomic paclitaxel has been launched. In addition to sorafenib this trial will test the concept of metronomic therapy in ACC. Metronomic chemotherapy targets tumor cells indirectly via inhibit- ing angiogenesis and vasculogenesis by continuously exposing the more slowly proliferating tumor endothelial cells to cytotoxic therapy. Low-dose metronomic chemotherapy may offer several advantages, including low toxicity and theoretically treatment response irrespec- tive of the resistance profile of the tumor cell population.

The experience with immunotherapeutic approaches in ACC is still scarce. Two patients have been treated with dendritic cells loaded with tumor lysate. An antigen-specific Th1 immunity was demon- strated, but no clinical response was seen (Papewalis et al., 2006). However, studies in other tumors indicate renaissance of cancer immunotherapy (Finn, 2008; Weiner, 2008) and ACCs express several interesting targets for a specific immunotherapeutic approach (e.g. steroidogenic factor 1, survivin) (Sbiera et al., 2008).

In conclusion, despite the disappointing first experience with “targeted therapies” in ACC, it is likely that these emerging new drugs hold promise also for this disease. Of particular interest are IGF1 receptor inhibitors and multiple TKI that attack several intracellular and extracellular targets.

6. Malignant pheochromocytoma/paraganglioma

Pheochromocytoma and paraganglioma are catecholamine- producing tumors of chromaffin cells that occur within the adrenal medulla or the sympathetic nervous system in chest, abdomen or pelvis (Lenders et al., 2005). According to the 2004 WHO classifica- tion, adrenal tumors are classified as pheochromocytomas whereas extraadrenal tumors are termed paragangliomas (DeLellis et al., 2004). As there are no clinical, biochemical and histopathological differences between adrenal pheochromocytomas and sympathetic paragangliomas, both will here be regarded as the same entity. An Australian autopsy series has revealed a prevalence of 0.05% of all

autopsies (McNeil et al., 2000), but the annual incidence of clinically detected catecholamine-producing tumors is much lower (about 2-5 per million population) and only about 15% of these tumors are malignant (Proye et al., 1994; Mannelli et al., 1999; Amar et al., 2005b). The percentage of malignant tumors in paraganglioma (about 40%) is much higher than in pheochromocytoma (about 10%). However, no clear histopathological criteria are available to distinguish benign from malignant lesions and malignancy is only established beyond doubt by the presence of distant metastases. Five genes are associated with familial pheochromocytomas and paragangliomas: von Hippel- Lindau (vHL) gene, RET proto-oncogene in multiple endocrine neoplasia type 2 (MEN2), neurofibromatosis type 1 (NF1) gene (von Recklingshausen’s disease) and genes encoding succinate dehydro- genase subunits D (SDHD) and B (SDHB) (paraganglioma syndrome 1 and 4). Of note, propensity to malignancy is dependent on the genetic background of the tumors. In sporadic tumors, only 6% are malignant and the likelihood of malignancy is even lower in patients with RET, vHL and SDHD gene mutations. However, probably more than 40% of patients with SDHB mutation will develop distant metastases.

6.1. Current treatment standards

After preoperative treatment to block the effects of catecholamine excess (e.g. with a-adrenoceptor antagonists) surgery is the treat- ment of choice in most patients and can potentially provide cure. However, in advanced disease curative resection can be seldom achieved (Ahlman 2006; Scholz et al., 2007; Adler et al., 2008). Reduction of tumor burden palliates symptoms and can facilitate subsequent radiotherapy or chemotherapy. However, a survival advantage of debulking is still unproven (Pacak et al., 2007). To date, 131I-labeled MIBG therapy is the single most valuable adjunct to surgical treatment of malignant pheochromocytoma (Loh et al., 1997; Chrisoulidou et al., 2007). Approximately 60% of metastatic sites are 131I-MIBG avid and in a recent metaanalysis including 166 patients the objective response rate was 30% and disease stabilization was achieved in an additional 43% of patients (Chrisoulidou et al., 2007). Experience with cytotoxic chemotherapy is limited and the best published results were seen with a combination of cyclophosphamide, vincristin, and darcarbazine leading to tumor regression and symptom relief in up to 50% of patients (Averbuch et al., 1988). However,

Table 8 Selection of currently active clinical trials in ACC.ª

Agents	Rationale	Trial ID trial acronym	Location contact
EDP-M vs. Sz-M	Establishment of a first line cytotoxic drug regimen (phase III)	NCT00094497 FIRM-ACT	International Fassnacht_m@medizin. uni-wuerzburg.de
Mitotane vs. observation Sunitinib	Adjuvant mitotane after R0 resection (phase III)	NCT00777244 ADIUVO	International terzolo@usa.net
	Multiple TKIb (phase II)	NCT00453895 SIRAC	Germany
			Fassnacht_m@medizin. uni-wuerzburg.de
Sorafenib and metronomic paclitaxel	Multiple TKIb in combination with metronomic	NCT00786110 PAXO	Europe alfredo. berruti@gmail.com
	chemotherapy (phase II) IGF-R1 antibody in addition to mitotane in first line systemic treatment (randomized phase II)
Mitotane vs. mitotane + IMC-A12		NCT00810537	USA ghammer@med. umich.edu
Tariquidar, mitotane, doxorubicin, vincristine and etoposide	Inhibiting P-glycoprotein to improve response to cytotoxic drugs (phase II)	NCT00073996	USA National Cancer Institute

a As of December 30, 2008.

b See Table 2.

responses are usually short-lived, and treatment is valuable mainly for patients with symptomatic disease (Huang et al., 2008). External- beam irradiation of bone metastases and arterial embolization or chemoembolization, cryoablation, and radiofrequency ablation of hepatic and other lesions are treatment alternatives (Pacak et al., 2001; Eisenhofer et al., 2004; Scholz et al., 2007).

In all patients, hypertension and catecholamine-dependent symp- toms should be controlled by medical treatment (Pacak, 2007). For this purpose «-adrenergic receptor blockade followed by ß-adrener- gic blockade are used, but calcium channel blockers may also be effective. In patients with extensive catecholamine excess inhibition of catecholamine synthesis with «-methyl-paratyrosine is often valu- able, but its toxicity is substantial clearly limiting its use (Adler et al., 2008).

The overall prognosis of malignant catecholamine-producing tumors is poor, but there is significant heterogeneity between patients. Survival of patients with metastatic lesions in liver and lungs tends to be shorter (<5 years) than of patients with bone metastases only (Pacak et al., 2007).

6.2. Molecular targets in catecholamine-producing tumors

Advances in molecular genetics continue to underscore the importance of hereditary factors in the development of pheochromo- cytomas and propensity to malignancy. As described above, germline mutations in 5 genes are clearly linked to pheochromocytoma/ paraganglioma and counting for the vast majority of familial catecholamine-producing tumors and for about 25% of seemingly sporadic tumors (Neumann et al., 2002; Amar et al., 2005a; Pacak et al., 2007). In addition, SDHC mutations (paraganglioma syndrome 3) lead to hormone inactive head and neck paraganglioma derived from parasympathic gangliomas (Niemann & Muller, 2000) and a recent case report described the correlation of a mutation of the prolyl hydroxylase domain 2 gene (PDH2) and paraganglioma (Ladroue et al., 2008). Several studies could demonstrate that gene expression varies significantly between groups (Eisenhofer et al., 2004; Dahia et al., 2005; Dahia 2006; Eisenhofer et al., 2008a). There is increasing evidence that catecholamine-producing tumors with VHL, SDHB or SDHD mutations share similar molecular features, which are clearly distinguishable from tumors with RET or NF-1 mutations. The first group is linked to dysregulation of hypoxia-inducible factor 1 (HIF-1) and activation of hypoxia-inducible target genes, although there is an ongoing discussion if this is true also for the subgroup of VHL patients with only pheochromocytoma (Hoffman et al., 2001; Eisenhofer et al., 2004; Dahia et al., 2005; Knauth et al., 2009). However, in general activation of HIF-2x appears more important than HIF-1x in most VHL tumors with the reverse in SDH tumors (Pollard et al., 2006). The ability to inhibit or regulate the effects of HIF activation may become a critical tool for controlling the respective tumors and recently first drugs have advanced to early clinical trials (Denko, 2008). Prominent target genes of HIF-1 are VEGFs. Several studies demonstrated that VEGFs are over-expressed in the majority of catecholamine-producing tumors and are highly expressed in malignant tumors (Zielke et al., 2002; Salmenkivi et al., 2003; Takekoshi et al., 2004; Brieger et al., 2005). Gimenez-Roqueplo et al. could show that mutations in the mitochondrial SDHB gene activate cellular hypoxia pathway that stimulate production of VEGFs (Gimenez-Roqueplo et al., 2002). The importance of VEGF for the angiogenesis of pheochromocytomas was also demonstrated in vitro studies (Middeke et al., 2002). In addition, malignant pheochromocytomas are characterized by increased expression of several other factors associated with angiogenesis (Favier et al., 2002). Accordingly, blocking of VEGF by antibodies led to inhibition of tumor angiogenesis and tumor growth in a pheochro- mocytoma xenograft mouse model (Zielke et al., 2002).

The lack of histological criteria for malignancy has initiated many studies to find markers that differentiate benign from malignant

catecholamine producing tumors. So far, several cancer-associated markers, such as p53 and Ki-67 (Brown et al., 1999; de Krijger et al., 1999) or neuroendocrine-related markers like chromogranin A (Rao et al., 2002), neuropeptide Y (Helman et al., 1989), activin, inhibin (Salmenkivi et al., 2001; Hofland et al., 2007), 3.4-dihydroxyphenyla- lanine or endothelin receptor type A and B (Watanabe et al., 1997; Favier et al., 2002) have been investigated, but none has been shown to be of reliable prognostic value. Accordingly, a very recent study in 48 patients could not find an impact of cell cycle and apoptosis regulators like p53, Bcl-2, mdm-2, cyclin D1, p21, and p27 in predicting malignancy and behavior of pheochromocytomas (Strong et al., 2008). In addition, two studies have explored chromosomal abnormalities in pheochromocy- tomas by comparative genomic hybridization (Dannenberg et al., 2000; Edstrom et al., 2000). However, alterations associated with metastatic disease were only seen in 50-60% of cases (vs. 21% in benign tumors).

More insight came from studies comparing DNA, RNA or protein in benign vs. malignant pheochromocytomas. Gene expression is strongly dependent on biochemical phenotype of the tumor. Malig- nant tumors produce predominantly norepinephrine and have similar to VHL-associated pheochromocytomas usually an exclusively nora- drenergic gene profile, whereas MEN2 tumors express mainly adrenergic genes (Eisenhofer et al., 2004; Eisenhofer et al., 2008a). A small gene-expression profiling study including nine benign and nine malignant pheochromocytomas identified approximately 100 genes distinguishing both groups, including only 16 genes up- regulated in malignant tumors (Thouennon et al., 2007). The probably most promising approach so far was made by an international group coordinated by the National Institute of Health analyzing gene expression data from 90 patients with pheochromocytoma with detailed clinical and biochemical annotation including 20 patients with malignant tumors (Brouwers et al., 2006). Up to now only preliminary results were published indicating that close to 90% of differentially expressed genes in benign and malignant primary pheochromocytomas are underexpressed in malignant compared to benign tumors (Brouwers et al., 2006). This finding fits with the observation of a less differentiated biochemical phenotype in malignant tumors, as characterized by lack of production of epi- nephrine and relatively high production of dopamine and its O- methylated metabolite methoxy-tyramine compared to norepinephr- ine (Eisenhofer et al., 2008b). However, the low rate of epinephrine producing malignant tumors may reflect the high prevalence of extra- adrenal malignant tumors which lack epinephrine secretion. In addition, the NIH study indicated that disproportionate numbers of differentially expressed genes between malignant and benign tumors are related to angiogenesis, translation, and signal transduction, whereas the comparison of malignant primary tumors with metas- tases indicated an importance of genes related to cell proliferation, cytoskeletal function, and regulation of transcription (Brouwers et al., 2006). The original database is available on request and may serve as valuable resource for further study by other researchers.

Using a new method utilizing low molecular weight protein profiles in serum samples of 33 patients with benign and 34 with malignant pheochromocytoma, Brouwers et al. were able to identify combinations of low molecular weight molecules that could distin- guish all metastatic form benign patient serum samples (Brouwers et al., 2005). However, these data need confirmation in an indepen- dent cohort.

The lack of established human pheochromocytoma cell lines and adequate animal models for malignant catecholamine producing tumors has hampered the research on tumorigenesis and novel treatment strategies in the past. In addition to the rat PC12 cell line established more than 30 years ago (Greene & Tischler, 1976) several different mouse pheochromocytoma cell lines were developed recently by knockout of the tumor suppressor gene NF1 (see Ahlman, 2006). In addition, in the last few years, first preclinical studies have been performed using rat and human pheochromocytoma cell lines or

xenografts to nude mice (Zielke et al., 2002; Gross et al., 2003). Furthermore, knockout of PTEN also predisposes to the development of pheochromocytomas (Stambolic et al., 2000; You et al., 2002). Although loss of heterozygosity for PTEN was found in only 4 of 32 investigated samples from human pheochromocytomas (Fassnacht et al., 2005; van Nederveen et al., 2006) the down-stream target of PTEN AKT was highly phosphorylated in most pheochromocytomas (Fassnacht et al., 2005) indicating the protein B kinase pathway as a potential target for therapy.

From a therapeutic point of view, also the overexpression of heat shock protein 90 (HSP90) and human telomerase (TERT) in malignant pheochromocytomas is of interest. HSP90 is strongly expressed in malignant pheochromocytomas (Boltze et al., 2003a) and a new class of anticancer drugs is under development to inhibit this protein (Powers & Workman, 2006; Powers & Workman, 2007). TERT, which also shows increased expression in malignant pheochromocytomas (Boltze et al., 2003b; Elder et al., 2003), may also serve as a future therapeutic target (Zimmermann & Martens, 2007). Another pre- clinical approach used human VHL tumor xenografts to demonstrate an antitumor effects of halofuginone an inhibitor of collagen synthesis and matrix metalloproteases (Gross et al., 2003).

The development of new somatostatin analogues like pasireotide raised again interest in the expression of somatostatin receptors in pheochromocytomas. Two studies could demonstrate that somatostatin receptor subtype 3 is the most abundant subtype in pheochromocytoma expressed also in the majority of malignant pheochromocytomas (Mundschenk et al., 2003; Unger et al., 2008). Accordingly, the multi- somatostatin receptor analogue SOM230 (pasireotide) inhibited cell growth in primary cultures of human pheochromocytomas (Pasquali et al., 2008).

6.3. Clinical experience with “emerging therapies”

Up to now, no single phase II or III trial investigating “new drugs” in malignant catecholamine producing tumors has been published (Table 9 and 10). The largest series reported in the last decade have focused on radionuclide therapy: 30 patients were treated with 131I-MIBG in a high dose regime (median single dose of 37 GBq and a median cumulative dose of 46 GBq). 4 of these patients experienced sustained complete remission and 15 sustained partial response, but >70% of patients developed grade 3 or 4 toxicity (Rose et al., 2003; Fitzgerald et al., 2006). Other ongoing studies investigate modified MIBG formulations or drugs in combination with MIBG (Table 10).

Table 9 Results using "targeted therapies" in malignant catecholamine producing tumors.

Agents	Rationale	n	Outcome (in evaluable patients)	Reference
131 I-MIBG	High dose (median cumulative dose 46 GBq)	30	CR 13%; PR 50%	Fitzgerald et al., 2006
Radiolabeled DOTATOC	Radionuclide therapy targeting SSR	28	PR 7%; SD 64%	Forrer et al., 2008
Octreotide	Targeting SSR	10	No biochemical and clinical response	Lamarre-Cliche et al., 2002
Sunitinib	Multiple TKIª	4	PR in 4 patients	Jimenez et al., 2009; Joshua et al., 2009
Everolimus	mTOR inhibitor	4	No response	Chrisoulidou et al., 2007; Fraenkel et al., 2008
Thalidomide + temozolomide	Anti-angiogenesis + cytotoxic drug	3	PR in 1 patient	Kulke et al., 2006
Imatinib	Inhibition of c-kit + PDGF	2	no response	Gross et al., 2006

n number of patients.

a See Table 2.

Table 10 Selection of currently active clinical trials in malignant catecholamine producing tumors.ª

Agents	Rationale	Trial ID	Location/contact
131I-MIBG plus sensitization medications vs. 131I-MIBG alone	Improvement of MIBG therapy (randomized phase II)	NCT00028106	National Institutes of Health Clinical Center (CC)
Ultratrace Iobenguane (131]-MIBG)	Improvement of MIBG therapy (phase I-II)	NCT00339131	USA, Canada Molecular Insight Pharmaceut.
131I-MIBG and arsenic trioxide	Improvement of MIBG therapy (phase II)	NCT00107289	Memorial Sloan-Kettering Cancer Center modaks@mskcc.org USA, Canada Jennifer. knox@uhn.on.ca
Sunitinib	Multiple TKIb	n.a.

n.a. not available.

a As of December 30, 2008.

b See Table 2.

Treatment with radioactive somatostatin analogues holds also some promise. In addition to anecdotal cases (Otte et al., 1999; Valkema et al., 2002), a series of 28 patients treated with radiolabeled DOTATOC has been published recently. Two patients had a partial response, 5 a minor response and 13 stable disease (Forrer et al., 2008). In contrast, treatment with non radioactive 20 mg slow release octreotide was without any measurable clinical and biochemical benefit (Lamarre-Cliche et al., 2002).

Some phase I/II trials studying new therapies also included single patients with malignant pheochromocytoma. Three patients were enrolled in a phase II study evaluating the effects of temozolomide, an orally available alkylating agent similar to dacarbazine, in combina- tion with thalidomide (Table 2) in patients with metastatic neuroen- docrine tumors. In one of these patients a partial response was observed (Kulke et al., 2006). More specific targeted therapy with imatinib mesylate (Table 2) has been tried in two patients with malignant pheochromocytomas, but no significant benefit was found (Gross et al., 2006). The same holds true for everolimus, an inhibitor of mTOR, that was not effective in 4 patients (Chrisoulidou et al., 2007; Fraenkel et al., 2008). The most promising but still immature results are reported with the multiple TKI sunitinib (Table 2). A patient suffering von Hippel-Lindau disease with malignant pheochromocy- toma and multiple renal and pancreatic tumors experienced a partial response after 6 months of treatment (Jimenez et al., 2009). In addition, a case series of three patients with metastatic catechola- mine-producing tumors treated with sunitinib were published. In all of them impressive partial responses has been achieved (Joshua et al., 2009). Accordingly, the authors currently organize a prospective phase II trial (Table 10).

In conclusion, it is difficult to predict which therapeutic approach is most promising for future treatment of malignant pheochromocy- toma. TKI targeting VEGF (like sunitinib) address key pathomechan- isms, but may induce further elevation of blood pressure in patients often already suffering from poorly controlled hypertension. Based on the molecular pathogenesis of pheochromocytoma, drugs interfering with protein kinase B (AKT) and HIF pathways may offer significant therapeutic potential and should be further evaluated in malignant pheochromocytoma (especially in patients with SDHB mutations).

7. Conclusions

Up to now with the exception of cinacalcet for parathyroid car- cinoma, none of the discussed new drugs and treatment strategies has become standard of care in any of the endocrine malignancies. However, the progress both in pre-clinical and clinical terms during the last decade is remarkable. In particular, in the field of advanced thyroid carcinoma not only the number of clinical trials but also the response rates are impressive and clearly superior to previous

therapies. Although results from phase III trials are still pending, there is no reason to doubt that the new “targeted therapies” will improve survival in MTC and probably also in advanced DTC. A major reason for the success of TKI in thyroid carcinoma is the well understood pathophysiology of these tumors including the identification of several key players for tumorigenesis (e.g. RET mutations in hereditary MTC). Therefore, an important future task consists in the characterization of critical intracellular pathways in endocrine tumor cells and in the surrounding tumor stroma for the other endocrine malignancies. In case of pheochromocytoma, the knowledge concern- ing potential new targets has greatly increased in the last few years, whereas the pathogenesis of ACC and parathyroid carcinoma is still only partly understood. True progress will also require a better understanding of the wide differences in biological behavior leading to the significant heterogeneity in clinical outcome within these tumor entities. In this context predicting tumor response to drugs (for both classical cytotoxic therapies and “targeted therapies”) will become of major importance and greatly influence quality of life and prognosis of patients, as individualized treatment will lead to a better risk-benefit ratio. It is expected that a rapidly increasing number of molecular markers with a potential to guide therapeutic decisions will be defined. Thus structures need to be developed to reliably examine these important markers in a given tumor and to provide the clinician with this increasingly crucial information in time. Another major task is to define combinations of drugs that act synergistically and further improve response to treatment and long- term outcome in patients with endocrine tumors without unaccep- table toxicity. For all this, it is of outmost importance to expand international collaborative networks of basic scientists and clinical researchers for endocrine malignancies. Only then it will be possible to significantly increase the number of well designed hypothesis- driven clinical trials which are required to take full advantage of the rapidly growing treatment opportunities.

References

Adler, J. T., Meyer-Rochow, G. Y., Chen, H., Benn, D. E., Robinson, B. G., Sippel, R. S., et al. (2008). Pheochromocytoma: current approaches and future directions. Oncologist 13(7), 779-793.

Ahlman, H. (2006). Malignant pheochromocytoma: state of the field with future projections. Ann N Y Acad Sci 1073, 449-464.

Ain, K. B. (1999). Anaplastic thyroid carcinoma: a therapeutic challenge. Semin Surg Oncol 16(1), 64-69.

Ain, K. B., Lee, C., & Williams, K. D. (2007). Phase II trial of thalidomide for therapy of radioiodine-unresponsive and rapidly progressive thyroid carcinomas. Thyroid 17(7), 663-670.

Ain, K. B., Taylor, K. D., Tofiq, S., & Venkataraman, G. (1997). Somatostatin receptor subtype expression in human thyroid and thyroid carcinoma cell lines. J Clin Endocrinol Metab 82(6), 1857-1862.

Airaksinen, M. S., & Saarma, M. (2002). The GDNF family: signalling, biological functions and therapeutic value. Nat Rev Neurosci 3(5), 383-394.

Akeno-Stuart, N., Croyle, M., Knauf, J. A., Malaguarnera, R., Vitagliano, D., Santoro, M., et al. (2007). The RET kinase inhibitor NVP-AST487 blocks growth and calcitonin gene expression through distinct mechanisms in medullary thyroid cancer cells. Cancer Res 67(14), 6956-6964.

Allolio, B., & Fassnacht, M. (2006). Clinical review: adrenocortical carcinoma: clinical update. J Clin Endocrinol Metab 91(6), 2027-2037.

Almeida, M. Q., Fragoso, M. C., Lotfi, C. F., Santos, M. G., Nishi, M. Y., Costa, M. H., et al. (2008). Expression of IGF-II and its receptor in pediatric and adult adrenocortical tumors. J Clin Endocrinol Metab 93(9), 3524-3531.

Alvarez-Nunez, F., Bussaglia, E., Mauricio, D., Ybarra, J., Vilar, M., Lerma, E., et al. (2006). PTEN promoter methylation in sporadic thyroid carcinomas. Thyroid 16(1), 17-23.

Amar, L., Bertherat, J., Baudin, E., Ajzenberg, C., Bressac-de Paillerets, B., Chabre, O., et al. (2005). Genetic testing in pheochromocytoma or functional paraganglioma. J Clin Oncol 23(34), 8812-8818.

Amar, L., Servais, A., Gimenez-Roqueplo, A. P., Zinzindohoue, F., Chatellier, G., & Plouin, P. F. (2005). Year of diagnosis, features at presentation, and risk of recurrence in patients with pheochromocytoma or secreting paraganglioma. J Clin Endocrinol Metab 90(4), 2110-2116.

Are, C., & Shaha, A. R. (2006). Anaplastic thyroid carcinoma: biology, pathogenesis, prognostic factors, and treatment approaches. Ann Surg Oncol 13(4), 453-464.

Arighi, E., Borrello, M. G., & Sariola, H. (2005). RET tyrosine kinase signaling in development and cancer. Cytokine Growth Factor Rev 16(4-5), 441-467.

Arnold, A., Kim, H. G., Gaz, R. D., Eddy, R. L., Fukushima, Y., Byers, M. G., et al. (1989). Molecular cloning and chromosomal mapping of DNA rearranged with the

parathyroid hormone gene in a parathyroid adenoma. J Clin Invest 83(6), 2034-2040.

Arnold, A. (1993). Genetic basis of endocrine disease 5. Molecular genetics of parathyroid gland neoplasia. J Clin Endocrinol Metab 77(5), 1108-1112.

Artinyan, A., Guzman, E., Maghami, E., Al-Sayed, M., D’Apuzzo, M., Wagman, L., et al. (2008). Metastatic parathyroid carcinoma to the liver treated with radio- frequency ablation and transcatheter arterial embolization. J Clin Oncol 26(24), 4039-4041.

Averbuch, S. D., Steakley, C. S., Young, R. C., Gelmann, E. P., Goldstein, D. S., Stull, R., et al. (1988). Malignant pheochromocytoma: effective treatment with a com- bination of cyclophosphamide, vincristine, and dacarbazine. Ann Intern Med 109(4), 267-273.

Bach, T. L., Barsigian, C., Chalupowicz, D. G., Busler, D., Yaen, C. H., Grant, D. S., et al. (1998). VE-cadherin mediates endothelial cell capillary tube formation in fibrin and collagen gels. Exp Cell Res 238(2), 324-334.

Bai, F., Pei, X. H., Pandolfi, P.P., & Xiong, Y.(2006). p18 Ink4c and Pten constrain a positive regulatory loop between cell growth and cell cycle control. Mol Cell Biol 26(12), 4564-4576.

Ball, D. W. (2007). Medullary thyroid cancer: therapeutic targets and molecular markers. Curr Opin Oncol 19(1), 18-23.

Barbaro, D., Boni, G., Meucci, G., Simi, U., Lapi, P., Orsini, P., et al. (2003). Radioiodine treatment with 30 mCi after recombinant human thyrotropin stimulation in thyroid cancer: effectiveness for postsurgical remnants ablation and possible role of iodine content in L-thyroxine in the outcome of ablation. J Clin Endocrinol Metab 88(9), 4110-4115.

Barlaskar, F. M., & Hammer, G. D. (2007). The molecular genetics of adrenocortical carcinoma. Rev Endocr Metab Disord 8(4), 343-348.

Barlaskar, F. M., Spalding, A. C., Heaton, J. H., Kuick, R., Kim, A. C., Thomas, D. G., et al. (2008). Preclinical targeting of the type 1 insulin-like growth factor receptor in adrenocortical carcinoma. J Clin Endocrinol Metab.

Baudin, E., & Schlumberger, M. (2007). New therapeutic approaches for metastatic thyroid carcinoma. Lancet Oncol 8(2), 148-156.

Bauer, K. S., Dixon, S. C., & Figg, W. D. (1998). Inhibition of angiogenesis by thalidomide requires metabolic activation, which is species-dependent. Biochem Pharmacol 55(11), 1827-1834.

Beauregard, D. A., Thelwall, P. E., Chaplin, D. J., Hill, S. A., Adams, G. E., & Brindle, K. M. (1998). Magnetic resonance imaging and spectroscopy of combretastatin A4 prodrug-induced disruption of tumour perfusion and energetic status. Br J Cancer 77(11), 1761-1767.

Bell, D. W., Varley, J. M., Szydlo, T. E., Kang, D. H., Wahrer, D. C., Shannon, K. E., et al. (1999). Heterozygous germ line hCHK2 mutations in Li-Fraumeni syndrome. Science 286(5449), 2528-2531.

Belo, A. V., Ferreira, M. A., Bosco, A. A., Machado, R. D., & Andrade, S. P. (2001). Differential effects of thalidomide on angiogenesis and tumor growth in mice. In- flammation 25(2), 91-96.

Berg, G., Lindstedt, G., Suurkula, M., & Jansson, S. (2002). Radioiodine ablation and therapy in differentiated thyroid cancer under stimulation with recombinant human thyroid-stimulating hormone. J Endocrinol Invest 25(1), 44-52.

Bergholm, U., Bergstrom, R., & Ekbom, A. (1997). Long-term follow-up of patients with medullary carcinoma of the thyroid. Cancer 79(1), 132-138.

Bergstrom, M., Bonasera, T. A., Lu, L., Bergstrom, E., Backlin, C., Juhlin, C., et al. (1998). In vitro and in vivo primate evaluation of carbon-11-etomidate and carbon-11- metomidate as potential tracers for PET imaging of the adrenal cortex and its tumors. J Nucl Med 39(6), 982-989.

Berruti, A., Terzolo, M., Sperone, P., Pia, A., Casa, S. D., Gross, D. J., et al. (2005). Etoposide, doxorubicin and cisplatin plus mitotane in the treatment of advanced adrenocor- tical carcinoma: a large prospective phase II trial. Endocr Relat Cancer 12(3), 657-666.

Betea, D., Bradwell, A. R., Harvey, T. C., Mead, G. P., Schmidt-Gayk, H., Ghaye, B., et al. (2004). Hormonal and biochemical normalization and tumor shrinkage induced by anti-parathyroid hormone immunotherapy in a patient with metastatic parathyr- oid carcinoma. J Clin Endocrinol Metab 89(7), 3413-3420.

Betz, M. J., Shapiro, I., Fassnacht, M., Hahner, S., Reincke, M., & Beuschlein, F. (2005). Peroxisome proliferator-activated receptor-gamma agonists suppress adrenocorti- cal tumor cell proliferation and induce differentiation. J Clin Endocrinol Metab 90(7), 3886-3896.

Beuschlein, F., Fassnacht, M., Klink, A., Allolio, B., & Reincke, M. (2001). ACTH-receptor expression, regulation and role in adrenocortial tumor formation. Eur J Endocrinol 144(3), 199-206.

Biondi, B., Filetti, S., & Schlumberger, M. (2005). Thyroid-hormone therapy and thyroid cancer: a reassessment. Nat Clin Pract Endocrinol Metab 1(1), 32-40.

Boikos, S. A., & Stratakis, C. A. (2008). Molecular mechanisms of medullary thyroid carcinoma: current approaches in diagnosis and treatment. Histol Histopathol 23(1), 109-116.

Boltze, C., Lehnert, H., Schneider-Stock, R., Peters, B., Hoang-Vu, C., & Roessner, A. (2003). HSP90 is a key for telomerase activation and malignant transition in pheochromocytoma. Endocrine 22(3), 193-201.

Boltze, C., Mundschenk, J., Unger, N., Schneider-Stock, R., Peters, B., Mawrin, C., et al. (2003). Expression profile of the telomeric complex discriminates between benign and malignant pheochromocytoma. J Clin Endocrinol Metab 88(9), 4280-4286.

Bourlet, P., Dumousset, E., Nasser, S., Chabrot, P., Pezet, D., Thieblot, P., et al. (2007). Embolization of hepatic and adrenal metastasis to treat Cushing’s syndrome associated with medullary thyroid carcinoma: a case report. Cardiovasc Intervent Radiol 30(5), 1052-1055.

Bradwell, A. R., & Harvey, T. C. (1999). Control of hypercalcaemia of parathyroid carcinoma by immunisation. Lancet 353(9150), 370-373.

Brandi, M. L., Gagel, R. F., Angeli, A., Bilezikian, J. P., Beck-Peccoz, P., Bordi, C., et al. (2001). Guidelines for diagnosis and therapy of MEN type 1 and type 2. J Clin Endocrinol Metab 86(12), 5658-5671.

Breviario, F., Caveda, L., Corada, M., Martin-Padura, I., Navarro, P., Golay, J., et al. (1995). Functional properties of human vascular endothelial cadherin (7B4/cadherin-5), an endothelium-specific cadherin. Arterioscler Thromb Vasc Biol 15(8), 1229-1239.

Brieger, J., Bedavanija, A., Gosepath, J., Maurer, J., & Mann, W. J. (2005). Vascular endothelial growth factor expression, vascularization and proliferation in para- gangliomas. ORL J Otorhinolaryngol Relat Spec 67(2), 119-124.

Brierley, J., Tsang, R., Simpson, W. J., Gospodarowicz, M., Sutcliffe, S., & Panzarella, T. (1996). Medullary thyroid cancer: analyses of survival and prognostic factors and the role of radiation therapy in local control. Thyroid 6(4), 305-310.

Brouwers, F. M., Elkahloun, A. G., Munson, P. J., Eisenhofer, G., Barb, J., Linehan, W. M., et al. (2006). Gene expression profiling of benign and malignant pheochromocytoma. Ann N Y Acad Sci 1073, 541-556.

Brouwers, F. M., Petricoin, E. F., III, Ksinantova, L., Breza, J., Rajapakse, V., Ross, S., et al. (2005). Low molecular weight proteomic information distinguishes metastatic from benign pheochromocytoma. Endocr Relat Cancer 12(2), 263-272.

Brown, H. M., Komorowski, R. A., Wilson, S. D., Demeure, M. J., & Zhu, Y. R. (1999). Predicting metastasis of pheochromocytomas using DNA flow cytometry and immunohistochemical markers of cell proliferation: a positive correlation between MIB-1 staining and malignant tumor behavior. Cancer 86(8), 1583-1589.

Buchdunger, E., O’Reilly, T., & Wood, J. (2002). Pharmacology of imatinib (STI571). Eur J Cancer 38(Suppl 5), S28-36.

Bukowski, R. M., Sheeler, L., Cunningham, J., & Esselstyn, C. (1984). Successful combination chemotherapy for metastatic parathyroid carcinoma. Arch Intern Med 144(2), 399-400.

Busaidy, N. L., Jimenez, C., Habra, M. A., Schultz, P. N., El-Naggar, A. K., Clayman, G. L., et al. (2004). Parathyroid carcinoma: a 22-year experience. Head Neck 26(8), 716-726. Busnardo, B., & De Vido, D. (2000). The epidemiology and etiology of differentiated thyroid carcinoma. Biomed Pharmacother 54(6), 322-326.

Calandra, D. B., Chejfec, G., Foy, B. K., Lawrence, A. M., & Paloyan, E. (1984). Parathyroid carcinoma: biochemical and pathologic response to DTIC. Surgery 96(6), 1132-1137.

Cantini, G., Lombardi, A., Piscitelli, E., Poli, G., Ceni, E., Marchiani, S., et al. (2008). Rosiglitazone inhibits adrenocortical cancer cell proliferation by interfering with the IGF-IR intracellular signaling. PPAR Res 2008, 904041.

Capitosti, S. M., Hansen, T. P., & Brown, M. L. (2004). Thalidomide analogues demonstrate dual inhibition of both angiogenesis and prostate cancer. Bioorg Med Chem 12(2), 327-336.

Carlomagno, F., Vitagliano, D., Guida, T., Basolo, F., Castellone, M. D., Melillo, R. M., et al. (2003). Efficient inhibition of RET/papillary thyroid carcinoma oncogenic kinases by 4-amino-5-(4-chloro-phenyl)-7-(t-butyl)pyrazolo[3,4-d]pyrimidine (PP2). J Clin Endocrinol Metab 88(4), 1897-1902.

Carlomagno, F., Vitagliano, D., Guida, T., Ciardiello, F., Tortora, G., Vecchio, G., et al. (2002). ZD6474, an orally available inhibitor of KDR tyrosine kinase activity, efficiently blocks oncogenic RET kinases. Cancer Res 62(24), 7284-7290.

Carlomagno, F., Vitagliano, D., Guida, T., Napolitano, M., Vecchio, G., Fusco, A., et al. (2002). The kinase inhibitor PP1 blocks tumorigenesis induced by RET oncogenes. Cancer Res 62(4), 1077-1082.

Carlomagno, F., Guida, T., Anaganti, S., Vecchio, G., Fusco, A., Ryan, A. J., et al. (2004). Disease associated mutations at valine 804 in the RET receptor tyrosine kinase confer resistance to selective kinase inhibitors. Oncogene 23(36), 6056-6063.

Carlomagno, F., Anaganti, S., Guida, T., Salvatore, G., Troncone, G., Wilhelm, S. M., et al. (2006). BAY 43-9006 inhibition of oncogenic RET mutants. J Natl Cancer Inst 98(5), 326-334.

Carlomagno, F., Guida, T., Anaganti, S., Provitera, L., Kjaer, S., McDonald, N., et al. (2008). Identification of tyrosine 806 as a molecular determinant of RET kinase sensitivity to ZD6474. Endocr Relat Cancer 16(1), 233-241.

Carmeliet, P., & Jain, R. K. (2000). Angiogenesis in cancer and other diseases. Nature 407 (6801), 249-257.

Carmeliet, P., Lampugnani, M. G., Moons, L., Breviario, F., Compernolle, V., Bono, F., et al. (1999). Targeted deficiency or cytosolic truncation of the VE-cadherin gene in mice impairs VEGF-mediated endothelial survival and angiogenesis. Cell 98(2), 147-157.

Casey, M. B., Zhang, S., Jin, L., Kajita, S., & Lloyd, R. V. (2004). Expression of cyclooxygenase-2 and thromboxane synthase in non-neoplastic and neoplastic thyroid lesions. Endocr Pathol 15(2), 107-116.

Castellone, M. D., Carlomagno, F., Salvatore, G., & Santoro, M. (2008). Receptor tyrosine kinase inhibitors in thyroid cancer. Best Pract Res Clin Endocrinol Metab 22(6), 1023-1038.

Castro, P., Rebocho, A. P., Soares, R. J., Magalhaes, J., Roque, L., Trovisco, V., et al. (2006). PAX8-PPARgamma rearrangement is frequently detected in the follicular variant of papillary thyroid carcinoma. J Clin Endocrinol Metab 91(1), 213-220.

Caveda, L., Martin-Padura, I., Navarro, P., Breviario, F., Corada, M., Gulino, D., et al. (1996). Inhibition of cultured cell growth by vascular endothelial cadherin (cadherin-5/VE-cadherin). J Clin Invest 98(4), 886-893.

Cetani, F., Pardi, E., Borsari, S., Viacava, P., Dipollina, G., Cianferotti, L., et al. (2004). Genetic analyses of the HRPT2 gene in primary hyperparathyroidism: germline and somatic mutations in familial and sporadic parathyroid tumors. J Clin Endocrinol Metab 89(11), 5583-5591.

Chacon, R., Tossen, G., Loria, F. S., & Chacon, M. (2005). CASE 2. Response in a patient with metastatic adrenal cortical carcinoma with thalidomide. J Clin Oncol 23(7), 1579-1580.

Chaplin, D. J., Pettit, G. R., & Hill, S. A. (1999). Anti-vascular approaches to solid tumour therapy: evaluation of combretastatin A4 phosphate. Anticancer Res 19(1A), 189-195.

Chaplin, D. J., Pettit, G. R., Parkins, C. S., & Hill, S. A. (1996). Antivascular approaches to solid tumour therapy: evaluation of tubulin binding agents. Br J Cancer Suppl 27, S86-S88.

Chatal, J. F., Campion, L., Kraeber-Bodere, F., Bardet, S., Vuillez, J. P., Charbonnel, B., et al. (2006). Survival improvement in patients with medullary thyroid carcinoma who undergo pretargeted anti-carcinoembryonic-antigen radioimmunotherapy: a col- laborative study with the French Endocrine Tumor Group. J Clin Oncol 24(11), 1705-1711.

Chen, B. K., Ohtsuki, Y., Furihata, M., Takeuchi, T., Iwata, J., Liang, S. B., et al. (1999). Co- overexpression of p53 protein and epidermal growth factor receptor in human papillary thyroid carcinomas correlated with lymph node metastasis, tumor size and clinicopathologic stage. Int J Oncol 15(5), 893-898.

Chow, L. Q., & Eckhardt, S. G. (2007). Sunitinib: from rational design to clinical efficacy. J Clin Oncol 25(7), 884-896.

Chrisoulidou, A., Kaltsas, G., Ilias, I., & Grossman, A. B. (2007). The diagnosis and management of malignant phaeochromocytoma and paraganglioma. Endocr Relat Cancer 14(3), 569-585.

Clarke, S. E. (1991). [131I]metaiodobenzylguanidine therapy in medullary thyroid cancer: Guy’s Hospital experience. J Nucl Biol Med 35(4), 323-326.

Coelho, S. M., Carvalho, D. P., & Vaisman, M. (2007). New perspectives on the treatment of differentiated thyroid cancer. Arq Bras Endocrinol Metabol 51(4), 612-624.

Coelho, S. M., Corbo, R., Buescu, A., Carvalho, D. P., & Vaisman, M. (2004). Retinoic acid in patients with radioiodine non-responsive thyroid carcinoma. J Endocrinol Invest 27(4), 334-339.

Cohen, E. E., Needles, B. M., Cullen, K. J., Wong, S. J., Wade, J. L., Ivy, S. P., et al. (2008). Phase 2 study of sunitinib in refractory thyroid cancer. J Clin Oncol 26 suppl; abstr 6025.

Cohen, E. E., Rosen, L. S., Vokes, E. E., Kies, M. S., Forastiere, A. A., Worden, F. P., et al. (2008). Axitinib is an active treatment for all histologic subtypes of advanced thyroid cancer: results from a phase II study. J Clin Oncol 26(29), 4708-4713.

Coll, A. P., Fassnacht, M., Klammer, S., Hahner, S., Schulte, D. M., Piper, S., et al. (2006). Peripheral administration of the N-terminal pro-opiomelanocortin fragment 1-28 to Pomc-/- mice reduces food intake and weight but does not affect adrenal growth or corticosterone production. J Endocrinol 190(2), 515-525.

Conticello, C., Adamo, L., Giuffrida, R., Vicari, L., Zeuner, A., Eramo, A., et al. (2007). Proteasome inhibitors synergize with tumor necrosis factor-related apoptosis- induced ligand to induce anaplastic thyroid carcinoma cell death. J Clin Endocrinol Metab 92(5), 1938-1942.

Cooney, M. M., Savvides, P., Agarwala, S., Wang, D., Flick, S., Bergant, S., et al. (2006). Phase II study of combretastatin A4 phosphate (CA4P) in patients with advanced anaplastic thyroid carcinoma (ATC). J Clin Oncol 24, 300S.

Cooper, D. S., Doherty, G. M., Haugen, B. R., Kloos, R. T., Lee, S. L., Mandel, S. J., et al. (2006). Management guidelines for patients with thyroid nodules and differ- entiated thyroid cancer. Thyroid 16(2), 109-142.

Cooper, D. S., Specker, B., Ho, M., Sperling, M., Ladenson, P. W., Ross, D. S., et al. (1998). Thyrotropin suppression and disease progression in patients with differentiated thyroid cancer: results from the National Thyroid Cancer Treatment Cooperative Registry. Thyroid 8(9), 737-744.

Corada, M., Mariotti, M., Thurston, G., Smith, K., Kunkel, R., Brockhaus, M., et al. (1999). Vascular endothelial-cadherin is an important determinant of microvascular integrity in vivo. Proc Natl Acad Sci U S A 96(17), 9815-9820.

Cornetta, A. J., Russell, J. P., Cunnane, M., Keane, W. M., & Rothstein, J. L. (2002). Cyclooxygenase-2 expression in human thyroid carcinoma and Hashimoto’s thyroiditis. Laryngoscope 112(2), 238-242.

Costa, A. M., Herrero, A., Fresno, M. F., Heymann, J., Alvarez, J. A., Cameselle-Teijeiro, J., et al. (2008). BRAF mutation associated with other genetic events identifies a subset of aggressive papillary thyroid carcinoma. Clin Endocrinol (Oxf) 68(4), 618-634.

Croyle, M., Akeno, N., Knauf, J. A., Fabbro, D., Chen, X., Baumgartner, J. E., et al. (2008). RET/PTC-induced cell growth is mediated in part by epidermal growth factor receptor (EGFR) activation: evidence for molecular and functional interactions between RET and EGFR. Cancer Res 68(11), 4183-4191.

D’Amato, R. J., Lentzsch, S., Anderson, K. C., & Rogers, M. S. (2001). Mechanism of action of thalidomide and 3-aminothalidomide in multiple myeloma. Semin Oncol 28(6), 597-601.

D’Amato, R. J., Loughnan, M. S., Flynn, E., & Folkman, J. (1994). Thalidomide is an inhibitor of angiogenesis. Proc Natl Acad Sci U S A 91(9), 4082-4085.

Dahia, P. L. (2006). Evolving concepts in pheochromocytoma and paraganglioma. Curr Opin Oncol 18(1), 1-8.

Dahia, P. L., Ross, K. N., Wright, M. E., Hayashida, C. Y., Santagata, S., Barontini, M., et al. (2005). A HIF1alpha regulatory loop links hypoxia and mitochondrial signals in pheochromocytomas. PLOS Genet 1(1), 72-80.

Dannenberg, H., Speel, E. J., Zhao, J., Saremaslani, P., van Der Harst, E., Roth, J., et al. (2000). Losses of chromosomes 1p and 3q are early genetic events in the development of sporadic pheochromocytomas. Am J Pathol 157(2), 353-359.

Dark, G. G., Hill, S. A., Prise, V. E., Tozer, G. M., Pettit, G. R., & Chaplin, D. J. (1997). Combretastatin A-4, an agent that displays potent and selective toxicity toward tumor vasculature. Cancer Res 57(10), 1829-1834.

Davies, L., & Welch, H. G. (2006). Increasing incidence of thyroid cancer in the United States, 1973-2002. Jama 295(18), 2164-2167.

Dawson, S. J., Conus, N. M., Toner, G. C., Raleigh, J. M., Hicks, R. J., McArthur, G., et al. (2008). Sustained clinical responses to tyrosine kinase inhibitor sunitinib in thyroid carcinoma. Anticancer Drugs 19(5), 547-552.

de Castro, G., Jr., & Awada, A. (2006). Side effects of anti-cancer molecular-targeted therapies (not monoclonal antibodies). Curr Opin Oncol 18(4), 307-315.

De Crevoisier, R., Baudin, E., Bachelot, A., Leboulleux, S., Travagli, J. P., Caillou, B., et al. (2004). Combined treatment of anaplastic thyroid carcinoma with surgery,

chemotherapy, and hyperfractionated accelerated external radiotherapy. Int J Radiat Oncol Biol Phys 60(4), 1137-1143.

de Fraipont, F., El Atifi, M., Cherradi, N., Le Moigne, G., Defaye, G., Houlgatte, R., et al. (2005). Gene expression profiling of human adrenocortical tumors using complementary deoxyribonucleic acid microarrays identifies several candidate genes as markers of malignancy. J Clin Endocrinol Metab 90(3), 1819-1829.

de Fraipont, F., El Atifi, M., Gicquel, C., Bertagna, X., Chambaz, E. M., & Feige, J. J. (2000). Expression of the angiogenesis markers vascular endothelial growth factor-A, thrombospondin-1, and platelet-derived endothelial cell growth factor in human sporadic adrenocortical tumors: correlation with genotypic alterations. J Clin Endocrinol Metab 85(12), 4734-4741.

de Groot, J. W., Links, T. P., Plukker, J. T., Lips, C. J., & Hofstra, R. M. (2006). RET as a diagnostic and therapeutic target in sporadic and hereditary endocrine tumors. Endocr Rev 27(5), 535-560.

de Groot, J. W., Plaza Menacho, I., Schepers, H., Drenth-Diephuis, L. J., Osinga, J., Plukker, J. T., et al. (2006). Cellular effects of imatinib on medullary thyroid cancer cells harboring multiple endocrine neoplasia type 2A and 2B associated RET mutations. Surgery 139(6), 806-814.

de Groot, J. W., Zonnenberg, B. A., van Ufford-Mannesse, P. Q., de Vries, M. M., Links, T. P., Lips, C. J., et al. (2007). A phase II trial of imatinib therapy for metastatic medullary thyroid carcinoma. J Clin Endocrinol Metab 92(9), 3466-3469.

de Reyniès, A., Assié, G., Rickman, D. S., Tissier, F., Groussin, L., René-Corail, F., et al. (2009). Gene expression profiling reveals a new classification of adrenocortical tumors and identifies molecular predictors of malignancy and survival. J Clin Oncol 27(7), 1108-1115.

de Krijger, R. R., van der Harst, E., van der Ham, F., Stijnen, T., Dinjens, W. N., Koper, J. W., et al. (1999). Prognostic value of p53, bcl-2, and c-erbB-2 protein expression in phaeochromocytomas. J Pathol 188(1), 51-55.

Dejana, E. (1996). Endothelial adherens junctions: implications in the control of vascular permeability and angiogenesis. J Clin Invest 98(9), 1949-1953.

DeLellis, R. A., Lloyd, R. V., Heitz, P. U., & Eng, C. (2004). World Health Organization classification of tumours. Pathol Genet Tumours Endocr Organs 136.

Denekamp, J. (1993). Review article: angiogenesis, neovascular proliferation and vascu- lar pathophysiology as targets for cancer therapy. Br J Radiol 66(783), 181-196. Denko, N. C. (2008). Hypoxia, HIF1 and glucose metabolism in the solid tumour. Nat Rev Cancer 8(9), 705-713.

Di Cristofaro, J., Marcy, M., Vasko, V., Sebag, F., Fakhry, N., Wynford-Thomas, D., et al. (2006). Molecular genetic study comparing follicular variant versus classic papillary thyroid carcinomas: association of N-ras mutation in codon 61 with follicular variant. Hum Pathol 37(7), 824-830.

Diel, I. J., Solomayer, E. F., Costa, S. D., Gollan, C., Goerner, R., Wallwiener, D., et al. (1998). Reduction in new metastases in breast cancer with adjuvant clodronate treatment. N Engl J Med 339(6), 357-363.

DiGiammarino, E. L., Lee, A. S., Cadwell, C., Zhang, W., Bothner, B., Ribeiro, R. C., et al. (2002). A novel mechanism of tumorigenesis involving pH-dependent destabiliza- tion of a mutant p53 tetramer. Nat Struct Biol 9(1), 12-16.

Dohna, M., Reincke, M., Mincheva, A., Allolio, B., Solinas-Toldo, S., & Lichter, P. (2000). Adrenocortical carcinoma is characterized by a high frequency of chromosomal gains and high-level amplifications. Genes Chromosomes Cancer 28(2), 145-152.

Donis-Keller, H., Dou, S., Chi, D., Carlson, K. M., Toshima, K., Lairmore, T. C., et al. (1993). Mutations in the RET proto-oncogene are associated with MEN 2A and FMTC. Hum Mol Genet 2(7), 851-856.

Dow, K. H., Ferrell, B. R., & Anello, C. (1997). Quality-of-life changes in patients with thyroid cancer after withdrawal of thyroid hormone therapy. Thyroid 7(4), 613-619.

Dowlati, A., Robertson, K., Cooney, M., Petros, W. P., Stratford, M., Jesberger, J., et al. (2002). A phase I pharmacokinetic and translational study of the novel vascular targeting agent combretastatin a-4 phosphate on a single-dose intravenous schedule in patients with advanced cancer. Cancer Res 62(12), 3408-3416.

Dralle, H., Damm, I., Scheumann, G. F., Kotzerke, J., Kupsch, E., Geerlings, H., et al. (1994). Compartment-oriented microdissection of regional lymph nodes in medullary thyroid carcinoma. Surg Today 24(2), 112-121.

Druckenthaner, M., Schwarzer, C., Ensinger, C., Gabriel, M., Prommegger, R., Riccabona, G., et al. (2007). Evidence for somatostatin receptor 2 in thyroid tissue. Regul Pept 138(1), 32-39.

Durante, C., Haddy, N., Baudin, E., Leboulleux, S., Hartl, D., Travagli, J. P., et al. (2006). Long-term outcome of 444 patients with distant metastases from papillary and follicular thyroid carcinoma: benefits and limits of radioiodine therapy. J Clin Endocrinol Metab 91(8), 2892-2899.

Dvorakova, S., Vaclavikova, E., Sykorova, V., Vcelak, J., Novak, Z., Duskova, J., et al. (2008). Somatic mutations in the RET proto-oncogene in sporadic medullary thyroid carcinomas. Mol Cell Endocrinol 284(1-2), 21-27.

Dwight, T., Thoppe, S. R., Foukakis, T., Lui, W. O., Wallin, G., Hoog, A., et al. (2003). Involvement of the PAX8/peroxisome proliferator-activated receptor gamma rear- rangement in follicular thyroid tumors. J Clin Endocrinol Metab 88(9), 4440-4445.

Dziba, J. M., Marcinek, R., Venkataraman, G., Robinson, J. A., & Ain, K. B. (2002). Combretastatin A4 phosphate has primary antineoplastic activity against human anaplastic thyroid carcinoma cell lines and xenograft tumors. Thyroid 12(12), 1063-1070.

Edstrom, E., Mahlamaki, E., Nord, B., Kjellman, M., Karhu, R., Hoog, A., et al. (2000). Comparative genomic hybridization reveals frequent losses of chromosomes 1p and 3q in pheochromocytomas and abdominal paragangliomas, suggesting a common genetic etiology. Am J Pathol 156(2), 651-659.

Eisenhofer, G., Bornstein, S. R., Brouwers, F. M., Cheung, N. K., Dahia, P. L., de Krijger, R. R., et al. (2004). Malignant pheochromocytoma: current status and initiatives for future progress. Endocr Relat Cancer 11(3), 423-436.

Eisenhofer, G., Huynh, T. T., Elkahloun, A., Morris, J. C., Bratslavsky, G., Linehan, W. M., et al. (2008). Differential expression of the regulated catecholamine secretory pathway in different hereditary forms of pheochromocytoma. Am J Physiol Endocrinol Metab 295(5), E1223-E1233.

Eisenhofer, G., Lenders, J. W. M., Timmers, H., Mannelli, M., Siegert, G., Bornstein, S. R., et al. (2008). Biochemical profiling of chromaffin cell tumors: guide for genotyping and prediction of malignancy. J Hum Hypertens 22(suppl 1), S3.

Elder, E. E., Xu, D., Hoog, A., Enberg, U., Hou, M., Pisa, P., et al. (2003). KI-67 AND hTERT expression can aid in the distinction between malignant and benign pheochromo- cytoma and paraganglioma. Mod Pathol 16(3), 246-255.

Elisei, R., Ugolini, C., Viola, D., Lupi, C., Biagini, A., Giannini, R., et al. (2008). BRAF(V600E) mutation and outcome of patients with papillary thyroid carci- noma: a 15-year median follow-up study. J Clin Endocrinol Metab 93(10), 3943-3949.

Eng, C., Mulligan, L. M., Healey, C. S., Houghton, C., Frilling, A., Raue, F., et al. (1996). Heterogeneous mutation of the RET proto-oncogene in subpopulations of medullary thyroid carcinoma. Cancer Res 56(9), 2167-2170.

Eng, C. (1998). Genetics of Cowden syndrome: through the looking glass of oncology. Int J Oncol 12(3), 701-710.

Erdogan, M., Berdeli, A., Karadeniz, M., Ertan, Y., Cetinkalp, S., Saygili, F., et al. (2008). The prevalence of RET/PTC mutations in papillary thyroid cancers in Turkish population and its relation between tumor histopathology and prognostic factors. Exp Clin Endocrinol Diabetes 116(4), 225-230.

Esapa, C. T., Johnson, S. J., Kendall-Taylor, P., Lennard, T. W., & Harris, P.E. (1999). Prevalence of Ras mutations in thyroid neoplasia. Clin Endocrinol (Oxf) 50(4), 529-535.

Fagin, J. A. (2004). How thyroid tumors start and why it matters: kinase mutants as targets for solid cancer pharmacotherapy. J Endocrinol 183(2), 249-256.

Fagin, J. A. (2005). Genetics of papillary thyroid cancer initiation: implications for therapy.Trans Am Clin Climatol Assoc 116, 259-269 discussion 269-71.

Falchetti, A., Becherini, L., Martineti, V., Morelli, A., Benvenuti, S., Picariello, L., et al. (1999). Telomerase repeat amplification protocol (TRAP): a new molecular marker for parathyroid carcinoma. Biochem Biophys Res Commun 265(1), 252-255.

Falchetti, A., Franchi, A., Bordi, C., Mavilia, C., Masi, L., Cioppi, F., et al. (2005). Azidothymidine induces apoptosis and inhibits cell growth and telomerase activity of human parathyroid cancer cells in culture. J Bone Miner Res 20(3), 410-418.

Fassnacht, M., & Allolio, B. (in press). Clinical management of adrenocortical carcinoma. Best Practice & Research Clinical Endocrinology & Metabolism. doi:10.1016/j. beem.2008.10.008.

Fassnacht, M., Franke, A., Dettling, A., Hahner, S., Zink, M., Wudy, S., et al. (2002). Clodronate inhibits adrenocortical cell proliferation and P450c21 activity. J Endocrinol 174(3), 509-516.

Fassnacht, M., Hahner, S., Hansen, I. A., Kreutzberger, T., Zink, M., Adermann, K., et al. (2003). N-terminal Proopiomelanocortin acts as a mitogen in adrenocortical tumor cells and decreases adrenal steroidogenesis. J Clin Endocrinol Metab 88(5), 2171-2179.

Fassnacht, M., Hahner, S., Heinrich, B., Adam, P., Quinkler, M., Stroebel, P., et al. (2007). Epidermal growth factor receptor (EGFR) as a potential new target in the treatment of patients with adrenocortical carcinoma - results of pre-clinical studies. J Clin Oncol suppl; abstr #21024.

Fassnacht, M., Hahner, S., Polat, B., Koschker, A. C., Kenn, W., Flentje, M., et al. (2006). Efficacy of adjuvant radiotherapy of the tumor bed on local recurrence of adrenocortical carcinoma. J Clin Endocrinol Metab 91(11), 4501-4504.

Fassnacht, M., Johanssen, S., Quinkler, M., Bucsky, P., Willenberg, H. S., Beuschlein, F., et al. (2009). Limited prognostic value of the 2004 International Union Against Cancer staging classification for adrenocortical carcinoma: proposal for a Revised TNM Classification. Cancer 115(2), 243-250.

Fassnacht, M., Weismann, D., Ebert, S., Adam, P., Zink, M., Beuschlein, F., et al. (2005). AKT is highly phosphorylated in pheochromocytomas but not in benign adrenocortical tumors. J Clin Endocrinol Metab 90(7), 4366-4370.

Favier, J., Plouin, P. F., Corvol, P., & Gasc, J. M. (2002). Angiogenesis and vascular architecture in pheochromocytomas: distinctive traits in malignant tumors. Am J Pathol 161(4), 1235-1246.

Fellmer, P. T., Sato, K., Tanaka, R., Okamoto, T., Kato, Y., Kobayashi, M., et al. (1999). Vascular endothelial growth factor-C gene expression in papillary and follicular thyroid carcinomas.Surgery 126(6), 1056-1061 discussion 1061-2.

Fernandez-Ranvier, G. G., Khanafshar, E., Tacha, D., Wong, M., Kebebew, E., Duh, Q, Y., et al. (2008). Defining a molecular phenotype for benign and malignant parathyroid tumors. Cancer.

Ferruzzi, P., Ceni, E., Tarocchi, M., Grappone, C., Milani, S., Galli, A., et al. (2005). Thiazolidinediones inhibit growth and invasiveness of the human adrenocortical cancer cell line H295R. J Clin Endocrinol Metab 90(3), 1332-1339.

Finn, O. J. (2008). Cancer immunology. N Engl J Med 358(25), 2704-2715.

Fitzgerald, P. A., Goldsby, R. E., Huberty, J. P., Price, D. C., Hawkins, R. A., Veatch, J. J., et al. (2006). Malignant pheochromocytomas and paragangliomas: a phase II study of therapy with high-dose 131I-metaiodobenzylguanidine (131I-MIBG). Ann N Y Acad Sci 1073, 465-490.

Flynn, S. D., Murren, J. R., Kirby, W. M., Honig, J., Kan, L., & Kinder, B. K. (1992). P- glycoprotein expression and multidrug resistance in adrenocortical carcinoma. Surgery 112(6), 981-986.

Forrer, F., Riedweg, I., Maecke, H. R., & Mueller-Brand, J. (2008). Radiolabeled DOTATOC in patients with advanced paraganglioma and pheochromocytoma. Q J Nucl Med Mol Imaging 52(4), 334-340.

Fortunati, N., Catalano, M. G., Arena, K., Brignardello, E., Piovesan, A., & Boccuzzi, G. (2004). Valproic acid induces the expression of the Na+/I- symporter and iodine uptake in poorly differentiated thyroid cancer cells. J Clin Endocrinol Metab 89(2), 1006-1009.

Fraenkel, M., Yarom, N., Barak, D., & Gross, D. J. (2008). A study of RAD001 (everolimus) 10 mg/day in two patients with malignant pheochromocytoma. 5th annual ENETS conference Paris, France abstract C28.

Frank-Raue, K., Fabel, M., Delorme, S., Haberkorn, U., & Raue, F. (2007). Efficacy of imatinib mesylate in advanced medullary thyroid carcinoma. Eur J Endocrinol 157(2), 215-220. Franks, M. E., Macpherson, G. R., & Figg, W. D. (2004). Thalidomide. Lancet 363(9423), 1802-1811.

Fromigue, J., De Baere, T., Baudin, E., Dromain, C., Leboulleux, S., & Schlumberger, M. (2006). Chemoembolization for liver metastases from medullary thyroid carci- noma. J Clin Endocrinol Metab 91(7), 2496-2499.

Fukushima, T., & Takenoshita, S. (2005). Roles of RAS and BRAF mutations in thyroid carcinogenesis. Fukushima J Med Sci 51(2), 67-75.

Furuya, F., Shimura, H., Suzuki, H., Taki, K., Ohta, K., Haraguchi, K., et al. (2004). Histone deacetylase inhibitors restore radioiodide uptake and retention in poorly dif- ferentiated and anaplastic thyroid cancer cells by expression of the sodium/iodide symporter thyroperoxidase and thyroglobulin. Endocrinology 145(6), 2865-2875.

Fury, M. G., Solit, D. B., Su, Y. B., Rosen, N., Sirotnak, F. M., Smith, R. P., et al. (2007). A phase I trial of intermittent high-dose gefitinib and fixed-dose docetaxel in patients with advanced solid tumors. Cancer Chemother Pharmacol 59(4), 467-475.

Garcia-Rostan, G., Zhao, H., Camp, R. L., Pollan, M., Herrero, A., Pardo, J., et al. (2003). ras mutations are associated with aggressive tumor phenotypes and poor prognosis in thyroid cancer. J Clin Oncol 21(17), 3226-3235.

Garcia-Rostan, G., Costa, A. M., Pereira-Castro, I., Salvatore, G., Hernandez, R., Hermsem, M. J., et al. (2005). Mutation of the PIK3CA gene in anaplastic thyroid cancer. Cancer Res 65(22), 10199-10207.

Gaujoux, S., Tissier, F., Groussin, L., Libe, R., Ragazzon, B., Launay, P., et al. (2008). Wnt/ ss-catenin and cAMP/PKA signaling pathways alterations and somatic ss-catenin gene mutations in the progression of adrenocortical tumors. J Clin Endocrinol Metab 93(10), 4135-4140.

Gelman, L., Fruchart, J. C., & Auwerx, J. (1999). An update on the mechanisms of action of the peroxisome proliferator-activated receptors (PPARs) and their roles in inflammation and cancer. Cell Mol Life Sci 55(6-7), 932-943.

Gicquel, C., Raffin-Sanson, M. L., Gaston, V., Bertagna, X., Plouin, P. F., Schlumberger, M., et al. (1997). Structural and functional abnormalities at 11p15 are associated with the malignant phenotype in sporadic adrenocortical tumors: study on a series of 82 tumors. J Clin Endocrinol Metab 82(8), 2559-2565.

Gicquel, C., Bertagna, X., Gaston, V., Coste, J., Louvel, A., Baudin, E., et al. (2001). Molecular markers and long-term recurrences in a large cohort of patients with sporadic adrenocortical tumors. Cancer Res 61(18), 6762-6767.

Gill, A. J., Clarkson, A., Gimm, O., Keil,J., Dralle, H., Howell, V.M., et al. (2006). Loss of nuclear expression of parafibromin distinguishes parathyroid carcinomas and hyperparathyr- oidism-jaw tumor (HPT-JT) syndrome-related adenomas from sporadic parathyroid adenomas and hyperplasias. Am J Surg Pathol 30(9), 1140-1149.

Gimenez-Roqueplo, A. P., Favier, J., Rustin, P., Rieubland, C., Kerlan, V., Plouin, P. F., et al. (2002). Functional consequences of a SDHB gene mutation in an apparently sporadic pheochromocytoma. J Clin Endocrinol Metab 87(10), 4771-4774.

Giordano, T. J., Kuick, R., Else, T., Gauger, P. G., Vinco, M., Bauersfeld, J., et al. (2009). Molecular classification and prognostication of adrenocortical tumors by tran- scriptome profiling. Clin Cancer Res 15(2), 668-676.

Giordano, T. J., Thomas, D. G., Kuick, R., Lizyness, M., Misek, D. E., Smith, A. L., et al. (2003). Distinct transcriptional profiles of adrenocortical tumors uncovered by DNA microarray analysis. Am J Pathol 162(2), 521-531.

Giraudet, A. L., Vanel, D., Leboulleux, S., Auperin, A., Dromain, C., Chami, L., et al. (2007). Imaging medullary thyroid carcinoma with persistent elevated calcitonin levels. J Clin Endocrinol Metab 92(11), 4185-4190.

Glover, D. J., Shaw, L., Glick, J. H., Slatopolsky, E., Weiler, C., Attie, M., et al. (1985). Treatment of hypercalcemia in parathyroid cancer with WR-2721, S-2-(3- aminopropylamino)ethyl-phosphorothioic acid. Ann Intern Med 103(1), 55-57.

Goulart, B., Carr, L., Martins, R. G., Eaton, K., Kell, E., Wallace, S., et al. (2008). Phase II study of sunitinib in iodine refractory, well-differentiated thyroid cancer (WDTC) and metastatic medullary thyroid carcinoma (MTC). J Clin Oncol 26 suppl; abstr 6062.

Greenberg, V. L., Williams, J. M., Cogswell, J. P., Mendenhall, M., & Zimmer, S. G. (2001). Histone deacetylase inhibitors promote apoptosis and differential cell cycle arrest in anaplastic thyroid cancer cells. Thyroid 11(4), 315-325.

Greene, L. A., & Tischler, A. S. (1976). Establishment of a noradrenergic clonal line of rat adrenal pheochromocytoma cells which respond to nerve growth factor. Proc Natl Acad Sci U S A 73(7), 2424-2428.

Gross, D. J., Reibstein, I., Weiss, L., Slavin, S., Dafni, H., Neeman, M., et al. (2003). Treatment with halofuginone results in marked growth inhibition of a von Hippel- Lindau pheochromocytoma in vivo. Clin Cancer Res 9(10 Pt 1), 3788-3793.

Gross, D. J., Munter, G., Bitan, M., Siegal, T., Gabizon, A., Weitzen, R., et al. (2006). The role of imatinib mesylate (Glivec) for treatment of patients with malignant endocrine tumors positive for c-kit or PDGF-R. Endocr Relat Cancer 13(2), 535-540. Grozinger, C. M., & Schreiber, S. L. (2002). Deacetylase enzymes: biological functions and the use of small-molecule inhibitors. Chem Biol 9(1), 3-16.

Grumbach, M. M., Biller, B. M., Braunstein, G. D., Campbell, K. K., Carney, J. A., Godley, P. A., et al. (2003). Management of the clinically inapparent adrenal mass (“incidenta- loma”). Ann Intern Med 138(5), 424-429.

Gruning, T., Tiepolt, C., Zophel, K., Bredow, J., Kropp, J., & Franke, W. G. (2003). Retinoic acid for redifferentiation of thyroid cancer - does it hold its promise? Eur J Endocrinol 148(4), 395-402.

Grunstein, M. (1997). Histone acetylation in chromatin structure and transcription. Nature 389(6649), 349-352.

Grunwald, F., Menzel, C., Bender, H., Palmedo, H., Otte, R., Fimmers, R., et al. (1998). Redifferentiation therapy-induced radioiodine uptake in thyroid cancer. J Nucl Med 39(11), 1903-1906.

Gupta-Abramson, V., Troxel, A. B., Nellore, A., Puttaswamy, K., Redlinger, M., Ransone, K., et al. (2008). Phase II trial of sorafenib in advanced thyroid cancer. J Clin Oncol 26(29), 4714-4719.

Haak, H. R., van Seters, A. P., Moolenaar, A. J., & Fleuren, G. J. (1993). Expression of P- glycoprotein in relation to clinical manifestation, treatment and prognosis of adrenocortical cancer. Eur J Cancer 29A(7), 1036-1038.

Haddad, R. I., Krebs, A. D., Vasselli, J., Paz-Ares, L. G., & Robinson, B. (2008). A phase II open-label study of vandetanib in patients with locally advanced or metastatic hereditary medullary thyroid cancer. J Clin Oncol 26 suppl; abstr 6024.

Hahner, S., & Fassnacht, M. (2005). Mitotane for adrenocortical carcinoma treatment. Curr Opin Investig Drugs 6(4), 386-394.

Hahner, S., Schirbel, A., Kreissl, M., Fassnacht, M., Johanssen, S., Hänscheid, H., et al. (2009). 131I-Iodometomidate radiotherapy for metastatic adrenocortical carci- noma - first clinical experience. Endocrine Abstracts (20) OC1.3 (11th European Congress of Endocrinology).

Hahner, S., Stuermer, A., Kreissl, M., Reiners, C., Fassnacht, M., Haenscheid, H., et al. (2008). [123 I]Iodometomidate for molecular imaging of adrenocortical cyto- chrome P450 family 11B enzymes. J Clin Endocrinol Metab 93(6), 2358-2365.

Haigh, P. I., Ituarte, P. H., Wu, H. S., Treseler, P. A., Posner, M. D., Quivey, J. M., et al. (2001). Completely resected anaplastic thyroid carcinoma combined with adjuvant chemother- apy and irradiation is associated with prolonged survival. Cancer 91(12), 2335-2342.

Hakaim, A. G., & Esselstyn, C. B., Jr. (1993). Parathyroid carcinoma: 50-year experience at The Cleveland Clinic Foundation. Cleve Clin J Med 60(4), 331-335.

Hanscheid, H., Lassmann, M., Luster, M., Thomas, S. R., Pacini, F., Ceccarelli, C., et al. (2006). Iodine biokinetics and dosimetry in radioiodine therapy of thyroid cancer: procedures and results of a prospective international controlled study of ablation after rhTSH or hormone withdrawal. J Nucl Med 47(4), 648-654.

Haugen, B. R., Larson, L. L., Pugazhenthi, U., Hays, W. R., Klopper, J. P., Kramer, C. A., et al. (2004). Retinoic acid and retinoid X receptors are differentially expressed in thyroid cancer and thyroid carcinoma cell lines and predict response to treatment with retinoids. J Clin Endocrinol Metab 89(1), 272-280.

Helman, L. J., Cohen, P. S., Averbuch, S. D., Cooper, M. J., Keiser, H. R., & Israel, M. A. (1989). Neuropeptide Y expression distinguishes malignant from benign pheo- chromocytoma. J Clin Oncol 7(11), 1720-1725.

Hennings, J., Lindhe, O., Bergstrom, M., Langstrom, B., Sundin, A., & Hellman, P. (2006). [11C]metomidate positron emission tomography of adrenocortical tumors in correla- tion with histopathological findings. J Clin Endocrinol Metab 91(4), 1410-1414.

Herbst, R. S., Heymach, J. V., O’Reilly, M. S., Onn, A., & Ryan, A. J. (2007). Vandetanib (ZD6474): an orally available receptor tyrosine kinase inhibitor that selectively targets pathways critical for tumor growth and angiogenesis. Expert Opin Investig Drugs 16(2), 239-249.

Hisada, M., Garber, J. E., Fung, C. Y., Fraumeni, J. F., Jr., & Li, F. P. (1998). Multiple primary cancers in families with Li-Fraumeni syndrome. J Natl Cancer Inst 90(8), 606-611. Hoff, P. M., Hoff, A. O., & Phan, A. (2006). Phase I/II trial of capecitabine (C), dacarbazine (D) and imatinib (I) (CDI) for patients (pts) metastatic thyroid carcinomas (MTC). J Clin Oncol abstr. 13048.

Hoffman, M. A., Ohh, M., Yang, H., Klco, J. M., Ivan, M., & Kaelin, W. G., Jr. (2001). von Hippel-Lindau protein mutants linked to type 2C VHL disease preserve the ability to downregulate HIF. Hum Mol Genet 10(10), 1019-1027.

Hofland, J., van Nederveen, F. H., Timmerman, M. A., Korpershoek, E., de Herder, W. W., Lenders, J. W., et al. (2007). Expression of activin and inhibin subunits, receptors and binding proteins in human pheochromocytomas: a study based on mRNA analysis and immunohistochemistry. Clin Endocrinol (Oxf) 66(3), 335-340.

Hou, P., Liu, D., Shan, Y., Hu, S., Studeman, K., Condouris, S., et al. (2007). Genetic alterations and their relationship in the phosphatidylinositol 3-kinase/Akt path- way in thyroid cancer. Clin Cancer Res 13(4), 1161-1170.

Hou, P., Ji, M., & Xing, M. (2008). Association of PTEN gene methylation with genetic alterations in the phosphatidylinositol 3-kinase/AKT signaling pathway in thyroid tumors. Cancer 113(9), 2440-2447.

Howell, V. M., Gill, A., Clarkson, A., Nelson, A. E., Dunne, R., Delbridge, L. W., et al. (2009). Accuracy of combined protein gene product 9.5 and parafibromin markers for immunohistochemical diagnosis of parathyroid carcinoma. J Clin Endocrinol Metab 94(2), 434-441.

Hsi, E. D., Zukerberg, L. R., Yang, W. I., & Arnold, A. (1996). Cyclin D1/PRAD1 expression in parathyroid adenomas: an immunohistochemical study. J Clin Endocrinol Metab 81(5), 1736-1739.

Huang, H., Abraham, J., Hung, E., Averbuch, S., Merino, M., Steinberg, S. M., et al. (2008). Treatment of malignant pheochromocytoma/paraganglioma with cyclophospha- mide, vincristine, and dacarbazine: recommendation from a 22-year follow-up of 18 patients. Cancer 113(8), 2020-2028.

Hundahl, S. A., Fleming, I. D., Fremgen, A. M., & Menck, H. R. (1998). A National Cancer Data Base report on 53,856 cases of thyroid carcinoma treated in the U.S., 1985- 1995. Cancer 83(12), 2638-2648.

Ichihara, M., Murakumo, Y., & Takahashi, M. (2004). RET and neuroendocrine tumors. Cancer Lett 204(2), 197-211.

Imanishi, R., Ohtsuru, A., Iwamatsu, M., Iioka, T., Namba, H., Seto, S., et al. (2002). A histone deacetylase inhibitor enhances killing of undifferentiated thyroid carci- noma cells by p53 gene therapy. J Clin Endocrinol Metab 87(10), 4821-4824.

Inai, T., Mancuso, M., Hashizume, H., Baffert, F., Haskell, A., Baluk, P., et al. (2004). Inhibition of vascular endothelial growth factor (VEGF) signaling in cancer causes loss of endothelial fenestrations, regression of tumor vessels, and appearance of basement membrane ghosts. Am J Pathol 165(1), 35-52.

Iten, F., Muller, B., Schindler, C., Rochlitz, C., Oertli, D., Macke, H. R., et al. (2007). Response to [90Yttrium-DOTA]-TOC treatment is associated with long-term survival benefit in metastasized medullary thyroid cancer: a phase II clinical trial. Clin Cancer Res 13(22 Pt 1), 6696-6702.

Jemal, A., Siegel, R., Ward, E., Hao, Y., Xu, J., Murray, T., et al. (2008). Cancer statistics, 2008. CA Cancer J Clin 58(2), 71-96.

Jeong, H., Kim, Y. R., Kim, K. N., Choe, J. G., Chung, J. K., & Kim, M. K. (2006). Effect of all- trans retinoic acid on sodium/iodide symporter expression, radioiodine uptake and gene expression profiles in a human anaplastic thyroid carcinoma cell line. Nucl Med Biol 33(7), 875-882.

Jimenez, C., Cabanillas, M. E., Santarpia, L., Jonasch, E., Kyle, K. L., Lano, E. A., et al. (2009). Use of the tyrosine kinase inhibitor sunitinib in a patient with von Hippel-Lindau disease: targeting angiogenic factors in pheochromocytoma and other von Hippel-Lindau disease-related tumors. J Clin Endocrinol Metab 94(2), 386-391.

Joshua, A. M., Ezzat, S., Asa, S. L., Evans, A., Broom, R., Freeman, M., et al. (2009). Rationale and evidence for sunitnib in the treatment of malignant paraganglioma/ pheochromocytoma (MPP). J Clin Endocrinol Metab 94(1), 5-9.

Juhlin, C. C., Villablanca, A., Sandelin, K., Haglund, F., Nordenstrom, J., Forsberg, L., et al. (2007). Parafibromin immunoreactivity: its use as an additional diagnostic marker for parathyroid tumor classification. Endocr Relat Cancer 14(2), 501-512.

Kaltsas, G. A., Papadogias, D., Makras, P., & Grossman, A. B. (2005). Treatment of advanced neuroendocrine tumours with radiolabelled somatostatin analogues. Endocr Relat Cancer 12(4), 683-699.

Kamio, T., Shigematsu, K., Sou, H., Kawai, K., & Tsuchiyama, H. (1990). Immunohisto- chemical expression of epidermal growth factor receptors in human adrenocortical carcinoma. Hum Pathol 21(3), 277-282.

Kebebew, E., & Clark, O. H. (2000). Medullary thyroid cancer. Curr Treat Options Oncol 1(4), 359-367.

Kebebew, E., Peng, M., Reiff, E., Treseler, P., Woeber, K. A., Clark, O. H., et al. (2006). A phase II trial of rosiglitazone in patients with thyroglobulin-positive and radio- iodine-negative differentiated thyroid cancer. Surgery 140(6), 960-966 discussion 966-7.

Kelleher, F. C., & McDermott, R. (2008). Response to sunitinib in medullary thyroid cancer. Ann Intern Med 148(7), 567.

Kerbel, R. S. (2008). Tumor angiogenesis. N Engl J Med 358(19), 2039-2049.

Khan, T. S., Imam, H., Juhlin, C., Skogseid, B., Grondal, S., Tibblin, S., et al. (2000). Streptozocin and o,p’DDD in the treatment of adrenocortical cancer patients: long- term survival in its adjuvant use. Ann Oncol 11(10), 1281-1287.

Khan, T. S., Sundin, A., Juhlin, C., Langstrom, B., Bergstrom, M., & Eriksson, B. (2003). 11C- metomidate PET imaging of adrenocortical cancer. Eur J Nucl Med Mol Imaging 30(3), 403-410.

Kihara, M., Miyauchi, A., Yamauchi, A., & Yokomise, H. (2004). Prognostic factors of anaplastic thyroid carcinoma. Surg Today 34(5), 394-398.

Kim, D. W., Jo, Y. S., Jung, H. S., Chung, H. K., Song, J. H., Park, K. C., et al. (2006). An orally administered multitarget tyrosine kinase inhibitor, SU11248, is a novel potent inhibitor of thyroid oncogenic RET/papillary thyroid cancer kinases. J Clin Endocrinol Metab 91(10), 4070-4076.

Kimura, E. T., Nikiforova, M. N., Zhu, Z., Knauf, J. A., Nikiforov, Y. E., & Fagin, J. A. (2003). High prevalence of BRAF mutations in thyroid cancer: genetic evidence for constitutive activation of the RET/PTC-RAS-BRAF signaling pathway in papillary thyroid carcinoma. Cancer Res 63(7), 1454-1457.

King, R. W., Deshaies, R. J., Peters, J. M., & Kirschner, M. W. (1996). How proteolysis drives the cell cycle. Science 274(5293), 1652-1659.

Kitamura, Y., Shimizu, K., Nagahama, M., Sugino, K., Ozaki, O., Mimura, T., et al. (1999). Immediate causes of death in thyroid carcinoma: clinicopathological analysis of 161 fatal cases. J Clin Endocrinol Metab 84(11), 4043-4049.

Kitazono, M., Bates, S., Fok, P., Fojo, T., & Blagosklonny, M. V. (2002). The histone deacetylase inhibitor FR901228 (desipeptide) restores expression and function of pseudo-null p53. Cancer Biol Ther 1(6), 665-668.

Kitazono, M., Robey, R., Zhan, Z., Sarlis, N. J., Skarulis, M. C., Aikou, T., et al. (2001). Low concentrations of the histone deacetylase inhibitor, depsipeptide (FR901228), increase expression of the Na(+)/I(-) symporter and iodine accumulation in poorly differentiated thyroid carcinoma cells. J Clin Endocrinol Metab 86(7), 3430-3435.

Klopper, J. P., Berenz, A., Hays, W. R., Sharma, V., Pugazhenthi, U., Janssen, J., et al. (2008). In vivo and microarray analysis of rexinoid-responsive anaplastic thyroid carcinoma. Clin Cancer Res 14(2), 589-596.

Klopper, J. P., Hays, W. R., Sharma, V., Baumbusch, M. A., Hershman, J. M., & Haugen, B. R. (2004). Retinoid X receptor-gamma and peroxisome proliferator-activated recep- tor-gamma expression predicts thyroid carcinoma cell response to retinoid and thiazolidinedione treatment. Mol Cancer Ther 3(8), 1011-1020.

Klubo-Gwiezdzinska, J., Junik, R., Kopczynska, E., Juraniec, O., & Kardymowicz, H. (2007). The comparison of serum vascular endothelial growth factor levels between patients with metastatic and non-metastatic thyroid cancer, and patients with nontoxic multinodular goiter. Eur J Endocrinol 157(4), 521-527.

Knauth, K., Cartwright, E., Freund, S. M., Bycroft, M., & Buchberger, A. (2009). VHL mutations linked to type 2C von Hippel-Lindau disease cause extensive structural perturbations in pVHL. J Biol Chem 284(16), 10514-10522.

Kober, F., Hermann, M., & Handler, A. (2007). Effect of sorafenib in symptomatic metastatic medullary thyroid cancer. J Clin Oncol abstr. 14065.

Koch, C. A., Brouwers, F. M., Vortmeyer, A. O., Tannapfel, A., Libutti, S. K., Zhuang, Z., et al. (2006). Somatic VHL gene alterations in MEN2-associated medullary thyroid carcinoma. BMC Cancer 6, 131.

Kohler, G., & Milstein, C. (1975). Continuous cultures of fused cells secreting antibody of predefined specificity. Nature 256(5517), 495-497.

Kohlfuerst, S., Igerc, I., Gallowitsch, H. J., Gomez, I., Kresnik, E., Matschnig, S., et al. (2006). Is there a role for sandostatin treatment in patients with progressive thyroid cancer and iodine-negative but somatostatin-receptor-positive metas- tases? Thyroid 16(11), 1113-1119.

Kolomecki, K., Stepien, H., Bartos, M., & Kuzdak, K. (2001). Usefulness of VEGF, MMP-2, MMP-3 and TIMP-2 serum level evaluation in patients with adrenal tumours. En- docr Regul 35(1), 9-16.

Koyano, H., Shishiba, Y., Shimizu, T., Suzuki, N., Nakazawa, H., Tachibana, S., et al. (1994). Successful treatment by surgical removal of bone metastasis producing PTH: new approach to the management of metastatic parathyroid carcinoma. Intern Med 33(11), 697-702.

Kroll, T. G., Sarraf, P., Pecciarini, L., Chen, C. J., Mueller, E., Spiegelman, B. M., et al. (2000). PAX8-PPARgamma1 fusion oncogene in human thyroid carcinoma [corrected]. Science 289(5483), 1357-1360.

Kulke, M. H., Stuart, K., Enzinger, P. C., Ryan, D. P., Clark, J. W., Muzikansky, A., et al. (2006). Phase II study of temozolomide and thalidomide in patients with metastatic neuroendocrine tumors. J Clin Oncol 24(3), 401-406.

Kurebayashi, J., Tanaka, K., Otsuki, T., Moriya, T., Kunisue, H., Uno, M., et al. (2000). All- trans-retinoic acid modulates expression levels of thyroglobulin and cytokines in a new human poorly differentiated papillary thyroid carcinoma cell line, KTC-1. J Clin Endocrinol Metab 85(8), 2889-2896.

Ladroue, C., Carcenac, R., Leporrier, M., Gad, S., Le Hello, C., Galateau-Salle, F., et al. (2008). PHD2 mutation and congenital erythrocytosis with paraganglioma. N Engl J Med 359(25), 2685-2692.

Lamarre-Cliche, M., Gimenez-Roqueplo, A. P., Billaud, E., Baudin, E., Luton, J. P., & Plouin, P. F. (2002). Effects of slow-release octreotide on urinary metanephrine excretion and plasma chromogranin A and catecholamine levels in patients with malignant or recurrent phaeochromocytoma. Clin Endocrinol (Oxf) 57(5), 629-634.

Latronico, A. C., Reincke, M., Mendonca, B. B., Arai, K., Mora, P., Allolio, B., et al. (1995). No evidence for oncogenic mutations in the adrenocorticotropin receptor gene in human adrenocortical neoplasms. J Clin Endocrinol Metab 80(3), 875-877.

Lenders, J. W., Eisenhofer, G., Mannelli, M., & Pacak, K. (2005). Phaeochromocytoma. Lancet 366(9486), 665-675.

Li, F. P., & Fraumeni, J. F., Jr. (1969). Soft-tissue sarcomas, breast cancer, and other neoplasms. A familial syndrome? Ann Intern Med 71(4), 747-752.

Liaw, D., Marsh, D. J., Li, J., Dahia, P. L., Wang, S. I., Zheng, Z., et al. (1997). Germline mutations of the PTEN gene in Cowden disease, an inherited breast and thyroid cancer syndrome. Nat Genet 16(1), 64-67.

Libe, R., Fratticci, A., & Bertherat, J. (2007). Adrenocortical cancer: pathophysiology and clinical management. Endocr Relat Cancer 14(1), 13-28.

Light, K., Jenkins, P. J., Weber, A., Perrett, C., Grossman, A., Pistorello, M., et al. (1995). Are activating mutations of the adrenocorticotropin receptor involved in adrenal cortical neoplasia? Life Sci 56(18), 1523-1527.

Liu, Z., Hou, P., Ji, M., Guan, H., Studeman, K., Jensen, K., et al. (2008). Highly prevalent genetic alterations in receptor tyrosine kinases and phosphatidylinositol 3-kinase/ Akt and mitogen-activated protein kinase pathways in anaplastic and follicular thyroid cancers. J Clin Endocrinol Metab 93(8), 3106-3116.

Liu, D., Hu, S., Hou, P., Jiang, D., Condouris, S., & Xing, M. (2007). Suppression of BRAF/ MEK/MAP kinase pathway restores expression of iodide-metabolizing genes in thyroid cells expressing the V600E BRAF mutant. Clin Cancer Res 13(4), 1341-1349.

Liu, Y. Y., Stokkel, M. P., Morreau, H. A., Pereira, A. M., Romijn, J. A., & Smit, J. W. (2008). Radioiodine therapy after pretreatment with bexarotene for metastases of differentiated thyroid carcinoma. Clin Endocrinol (Oxf) 68(4), 605-609.

Loh, K. C., Fitzgerald, P. A., Matthay, K. K., Yeo, P. P., & Price, D. C. (1997). The treatment of malignant pheochromocytoma with iodine-131 metaiodobenzylguanidine (131I- MIBG): a comprehensive review of 116 reported patients. J Endocrinol Invest 20(11), 648-658.

Luster, M., Clarke, S. E., Dietlein, M., Lassmann, M., Lind, P., Oyen, W. J., et al. (2008). Guidelines for radioiodine therapy of differentiated thyroid cancer. Eur J Nucl Med Mol Imaging 35(10), 1941-1959.

Luster, M., Felbinger, R., Dietlein, M., & Reiners, C. (2005). Thyroid hormone withdrawal in patients with differentiated thyroid carcinoma: a one hundred thirty-patient pilot survey on consequences of hypothyroidism and a pharmacoeconomic comparison to recombinant thyrotropin administration. Thyroid 15(10), 1147-1155.

Luster, M., Lippi, F., Jarzab, B., Perros, P., Lassmann, M., Reiners, C., et al. (2005). rhTSH- aided radioiodine ablation and treatment of differentiated thyroid carcinoma: a comprehensive review. Endocr Relat Cancer 12(1), 49-64.

Lynch, T. J., Bell, D. W., Sordella, R., Gurubhagavatula, S., Okimoto, R. A., Brannigan, B. W., et al. (2004). Activating mutations in the epidermal growth factor receptor underlying responsiveness of non-small-cell lung cancer to gefitinib. N Engl J Med 350(21), 2129-2139.

Machens, A., & Dralle, H. (2006). Multiple endocrine neoplasia type 2 and the RET protooncogene: from bedside to bench to bedside. Mol Cell Endocrinol 247(1-2), 34-40.

Machens, A., Schneyer, U., Holzhausen, H. J., & Dralle, H. (2005). Prospects of remission in medullary thyroid carcinoma according to basal calcitonin level. J Clin Endocrinol Metab 90(4), 2029-2034.

Maher, E. R., & Reik, W. (2000). Beckwith-Wiedemann syndrome: imprinting in clusters revisited. J Clin Invest 105(3), 247-252.

Mallya, S. M., & Arnold, A. (2000). Cyclin D1 in parathyroid disease. Front Biosci 5, D367-D371.

Manie, S., Santoro, M., Fusco, A., & Billaud, M. (2001). The RET receptor: function in development and dysfunction in congenital malformation. Trends Genet 17(10), 580-589.

Mannelli, M., Ianni, L., Cilotti, A., & Conti, A. (1999). Pheochromocytoma in Italy: a multicentric retrospective study. Eur J Endocrinol 141(6), 619-624.

Marsee, D. K., Venkateswaran, A., Tao, H., Vadysirisack, D., Zhang, Z., Vandre, D. D., et al. (2004). Inhibition of heat shock protein 90, a novel RET/PTC1-associated protein, increases radioiodide accumulation in thyroid cells. J Biol Chem 279(42), 43990-43997.

Martelli, M. L., Iuliano, R., Le Pera, I., Sama, I., Monaco, C., Cammarota, S., et al. (2002). Inhibitory effects of peroxisome proliferator-activated receptor gamma on thyroid carcinoma cell growth. J Clin Endocrinol Metab 87(10), 4728-4735.

Mato, E., Matias-Guiu, X., Chico, A., Webb, S. M., Cabezas, R., Berna, L., et al. (1998). Somatostatin and somatostatin receptor subtype gene expression in medullary thyroid carcinoma. J Clin Endocrinol Metab 83(7), 2417-2420.

Matsui, J., Funahashi, Y., Uenaka, T., Watanabe, T., Tsuruoka, A., & Asada, M. (2008). Multi-kinase inhibitor E7080 suppresses lymph node and lung metastases of human mammary breast tumor MDA-MB-231 via inhibition of vascular endothelial growth factor-receptor (VEGF-R) 2 and VEGF-R3 kinase. Clin Cancer Res 14(17), 5459-5465.

Matsui, J., Yamamoto, Y., Funahashi, Y., Tsuruoka, A., Watanabe, T., Wakabayashi, T., et al. (2008). E7080, a novel inhibitor that targets multiple kinases, has potent antitumor activities against stem cell factor producing human small cell lung cancer H146, based on angiogenesis inhibition. Int J Cancer 122(3), 664-671.

McNeil, A. R., Blok, B. H., Koelmeyer, T. D., Burke, M. P., & Hilton, J. M. (2000). Phaeochromocytomas discovered during coronial autopsies in Sydney, Melbourne and Auckland. Aust N Z J Med 30(6), 648-652.

Mehta, R. G., Williamson, E., Patel, M. K., & Koeffler, H. P. (2000). A ligand of peroxisome proliferator-activated receptor gamma, retinoids, and prevention of preneoplastic mammary lesions. J Natl Cancer Inst 92(5), 418-423.

Middeke, M., Hoffmann, S., Hassan, I., Wunderlich, A., Hofbauer, L. C., & Zielke, A. (2002). In vitro and in vivo angiogenesis in PC12 pheochromocytoma cells is mediated by vascular endothelial growth factor. Exp Clin Endocrinol Diabetes 110(8), 386-392.

Minn, H., Salonen, A., Friberg, J., Roivainen, A., Viljanen, T., Langsjo, J., et al. (2004). Imaging of adrenal incidentalomas with PET using (11)C-metomidate and (18)F- FDG. J Nucl Med 45(6), 972-979.

Mitsiades, C. S., Poulaki, V., McMullan, C., Negri, J., Fanourakis, G., Goudopoulou, A., et al. (2005). Novel histone deacetylase inhibitors in the treatment of thyroid cancer. Clin Cancer Res 11(10), 3958-3965.

Mitsiades, C. S., McMillin, D., Kotoula, V., Poulaki, V., McMullan, C., Negri, J., et al. (2006). Antitumor effects of the proteasome inhibitor bortezomib in medullary and anaplastic thyroid carcinoma cells in vitro. J Clin Endocrinol Metab 91(10), 4013-4021.

Modigliani, E., Cohen, R., Campos, J. M., Conte-Devolx, B., Maes, B., Boneu, A., et al. (1998). Prognostic factors for survival and for biochemical cure in medullary thyroid carcinoma: results in 899 patients. The GETC Study Group. Groupe d’etude des tumeurs a calcitonine. Clin Endocrinol (Oxf) 48(3), 265-273.

Moley, J. F., Dilley, W. G., & DeBenedetti, M. K. (1997). Improved results of cervical reoperation for medullary thyroid carcinoma. Ann Surg 225(6), 734-740 discussion 740-3.

Moreira, A. L., Sampaio, E. P., Zmuidzinas, A., Frindt, P., Smith, K. A., & Kaplan, G. (1993). Thalidomide exerts its inhibitory action on tumor necrosis factor alpha by enhancing mRNA degradation. J Exp Med 177(6), 1675-1680.

Mosimann, C., Hausmann, G., & Basler, K. (2006). Parafibromin/Hyrax activates Wnt/ Wg target gene transcription by direct association with beta-catenin/Armadillo. Cell 125(2), 327-341.

Moyer, J. D., Barbacci, E. G., Iwata, K. K., Arnold, L., Boman, B., Cunningham, A., et al. (1997). Induction of apoptosis and cell cycle arrest by CP-358,774, an inhibitor of epidermal growth factor receptor tyrosine kinase. Cancer Res 57(21), 4838-4848.

Mrozek, E., Kloos, R. T., Ringel, M. D., Kresty, L., Snider, P., Arbogast, D., et al. (2006). Phase II study of celecoxib in metastatic differentiated thyroid carcinoma. J Clin Endocrinol Metab 91(6), 2201-2204.

Mulligan, L. M., Kwok, J. B., Healey, C. S., Elsdon, M. J., Eng, C., Gardner, E., et al. (1993). Germ-line mutations of the RET proto-oncogene in multiple endocrine neoplasia type 2A. Nature 363(6428), 458-460.

Mundschenk, J., Unger, N., Schulz, S., Hollt, V., Schulz, S., Steinke, R., et al. (2003). Somatostatin receptor subtypes in human pheochromocytoma: subcellular expression pattern and functional relevance for octreotide scintigraphy. J Clin Endocrinol Metab 88(11), 5150-5157.

Murphy, K. M., Chen, F., & Clark, D. P. (2008). Identification of immunohistochemical biomarkers for papillary thyroid carcinoma using gene expression profiling. Hum Pathol 39(3), 420-426.

Murphy, G. J., & Holder, J. C. (2000). PPAR-gamma agonists: therapeutic role in diabetes, inflammation and cancer. Trends Pharmacol Sci 21(12), 469-474.

Neumann, H. P., Bausch, B., McWhinney, S. R., Bender, B. U., Gimm, O., Franke, G., et al. (2002). Germ-line mutations in nonsyndromic pheochromocytoma. N Engl J Med 346(19), 1459-1466.

Niemann, S., & Muller, U. (2000). Mutations in SDHC cause autosomal dominant paraganglioma, type 3. Nat Genet 26(3), 268-270.

Nikiforova, M. N., Lynch, R. A., Biddinger, P. W., Alexander, E. K., Dorn, G. W., 2nd, Tallini, G., et al. (2003). RAS point mutations and PAX8-PPAR gamma rearrangement in thyroid tumors: evidence for distinct molecular pathways in thyroid follicular carcinoma. J Clin Endocrinol Metab 88(5), 2318-2326.

Nocera, M., Baudin, E., Pellegriti, G., Cailleux, A. F., Mechelany-Corone, C., & Schlumberger, M. (2000). Treatment of advanced medullary thyroid cancer with an alternating combination of doxorubicin-streptozocin and 5 FU-dacarbazine. Groupe d’Etude des Tumeurs a Calcitonine (GETC). Br J Cancer 83(6), 715-718. Otte, A., Herrmann, R., Heppeler, A., Behe, M., Jermann, E., Powell, P., et al. (1999). Yttrium-90 DOTATOC: first clinical results. Eur J Nucl Med 26(11), 1439-1447.

Pacak, K., Fojo, T., Goldstein, D. S., Eisenhofer, G., Walther, M. M., Linehan, W. M., et al. (2001). Radiofrequency ablation: a novel approach for treatment of metastatic pheochromocytoma. J Natl Cancer Inst 93(8), 648-649.

Pacak, K. (2007). Preoperative management of the pheochromocytoma patient. J Clin Endocrinol Metab 92(11), 4069-4079.

Pacak, K., Eisenhofer, G., Ahlman, H., Bornstein, S. R., Gimenez-Roqueplo, A. P., Grossman, A. B., et al. (2007). Pheochromocytoma: recommendations for clinical

practice from the first international symposium. October 2005. Nat Clin Pract Endocrinol Metab 3(2), 92-102.

Pacifico, F., Mauro, C., Barone, C., Crescenzi, E., Mellone, S., Monaco, M., et al. (2004). Oncogenic and anti-apoptotic activity of NF-kappa B in human thyroid carcinomas. J Biol Chem 279(52), 54610-54619.

Pacini, F., Molinaro, E., Castagna, M. G., Agate, L., Elisei, R., Ceccarelli, C., et al. (2003). Recombinant human thyrotropin-stimulated serum thyroglobulin combined with neck ultrasonography has the highest sensitivity in monitoring differentiated thyroid carcinoma. J Clin Endocrinol Metab 88(8), 3668-3673.

Pacini, F., Schlumberger, M., Dralle, H., Elisei, R., Smit, J. W., & Wiersinga, W. (2006). European consensus for the management of patients with differentiated thyroid carcinoma of the follicular epithelium. Eur J Endocrinol 154(6), 787-803.

Papewalis, C., Fassnacht, M., Willenberg, H. S., Domberg, J., Fenk, R., Rohr, U. P., et al. (2006). Dendritic cells as potential adjuvant for immunotherapy in adrenocortical carcinoma. Clin Endocrinol (Oxf) 65(2), 215-222.

Papewalis, C., Wuttke, M., Seissler, J., Meyer, Y., Kessler, C., Jacobs, B., et al. (2008). Dendritic cell vaccination with xenogenic polypeptide hormone induces tumor rejection in neuroendocrine cancer. Clin Cancer Res 14(13), 4298-4305.

Pasieka, J. L. (2003). Anaplastic thyroid cancer. Curr Opin Oncol 15(1), 78-83.

Pasieka, J. L., McEwan, A. J., & Rorstad, O. (2004). The palliative role of 131I-MIBG and 111In-octreotide therapy in patients with metastatic progressive neuroendocrine neoplasms. Surgery 136(6), 1218-1226.

Pasieka, Z., Stepien, H., Komorowski, J., Kolomecki, K., & Kuzdak, K. (2003). Evaluation of the levels of bFGF, VEGF, sICAM-1, and sVCAM-1 in serum of patients with thyroid cancer. Recent Results Cancer Res 162, 189-194.

Pasquali, D., Rossi, V., Conzo, G., Pannone, G., Bufo, P., De Bellis, A., et al. (2008). Effects of somatostatin analog SOM230 on cell proliferation, apoptosis, and catecholamine levels in cultured pheochromocytoma cells. J Mol Endocrinol 40(6), 263-271.

Pennell, N. A., Daniels, G. H., Haddad, R. I., Ross, D. S., Evans, T., Wirth, L. J., et al. (2008). A phase II study of gefitinib in patients with advanced thyroid cancer. Thyroid 18(3), 317-323.

Petrangolini, G., Cuccuru, G., Lanzi, C., Tortoreto, M., Belluco, S., Pratesi, G., et al. (2006). Apoptotic cell death induction and angiogenesis inhibition in large established medullary thyroid carcinoma xenografts by Ret inhibitor RPI-1. Biochem Pharmacol 72(4), 405-414.

Philips, J. C., Petite, C., Willi, J. P., Buchegger, F., & Meier, C. A. (2004). Effect of peroxisome proliferator-activated receptor gamma agonist, rosiglitazone, on dedifferentiated thyroid cancers. Nucl Med Commun 25(12), 1183-1186.

Polat, B., Fassnacht, M., Pfreundner, L., Guckenberger, M., Bratengeier, K., Johanssen, S., et al. (in press). Radiotherapy in adrenocortical carcinoma. Cancer Apr 28 [Electronic publication ahead of print]. doi: 10.1002/cncr.24331.

Pollard, P. J., El-Bahrawy, M., Poulsom, R., Elia, G., Killick, P., Kelly, G., et al. (2006). Expression of HIF-1alpha, HIF-2alpha (EPAS1), and their target genes in paraganglioma and pheochromocytoma with VHL and SDH mutations. J Clin Endocrinol Metab 91(11), 4593-4598.

Polverino, A., Coxon, A., Starnes, C., Diaz, Z., DeMelfi, T., Wang, L., et al. (2006). AMG 706, an oral, multikinase inhibitor that selectively targets vascular endothelial growth factor, platelet-derived growth factor, and kit receptors, potently inhibits angiogenesis and induces regression in tumor xenografts. Cancer Res 66(17), 8715-8721.

Powers, M. V., & Workman, P. (2006). Targeting of multiple signalling pathways by heat shock protein 90 molecular chaperone inhibitors. Endocr Relat Cancer 13(Suppl 1), S125-S135.

Powers, M. V., & Workman, P. (2007). Inhibitors of the heat shock response: biology and pharmacology. FEBS Lett 581(19), 3758-3769.

Pressacco, J., & Erlichman, C. (1993). Combination studies with 3’-azido-3’-deoxythy- midine (AZT) plus ICI D1694. Cytotoxic and biochemical effects. Biochem Pharmacol 46(11), 1989-1997.

Provenzano, M. J., Fitzgerald, M. P., Krager, K., & Domann, F. E. (2007). Increased iodine uptake in thyroid carcinoma after treatment with sodium butyrate and decitabine (5-Aza-dC). Otolaryngol Head Neck Surg 137(5), 722-728.

Proye, C. A., Vix, M., Jansson, S., Tisell, L. E., Dralle, H., & Hiller, W. (1994). “The” pheochromocytoma: a benign, intra-adrenal, hypertensive, sporadic unilateral tumor. Does it exist? World J Surg 18(4), 467-472.

Puxeddu, E., Mitsutake, N., Knauf, J. A., Moretti, S., Kim, H. W., Seta, K. A., et al. (2003). Microsomal prostaglandin E2 synthase-1 is induced by conditional expression of RET/PTC in thyroid PCCL3 cells through the activation of the MEK-ERK pathway. J Biol Chem 278(52), 52131-52138.

Quinkler, M., Hahner, S., Wortmann, S., Johanssen, S., Adam, P., Ritter, C., et al. (2008). Treatment of advanced adrenocortical carcinoma with erlotinib plus gemcitabine. J Clin Endocrinol Metab 93(6), 2057-2062.

Quiros, R. M., Ding, H. G., Gattuso, P., Prinz, R. A., & Xu, X. (2005). Evidence that one subset of anaplastic thyroid carcinomas are derived from papillary carcinomas due to BRAF and p53 mutations. Cancer 103(11), 2261-2268.

Rabes, H. M., Demidchik, E. P., Sidorow, J. D., Lengfelder, E., Beimfohr, C., Hoelzel, D., et al. (2000). Pattern of radiation-induced RET and NTRK1 rearrangements in 191 post- chernobyl papillary thyroid carcinomas: biological, phenotypic, and clinical implications. Clin Cancer Res 6(3), 1093-1103.

Rao, F., Keiser, H. R., & O’Connor, D. T. (2002). Malignant and benign pheochromocy- toma: chromaffin granule transmitters and the response to medical and surgical treatment. Ann N Y Acad Sci 971, 530-532.

Ravaud, A., de la Fouchardiere, C., Courbon, F., Asselineau, J., Klein, M., Nicoli-Sire, P., et al. (2008). Sunitinib in patients with refractory advanced thyroid cancer: the THYSU phase II trial. J Clin Oncol 26 suppl; abstr 6058.

Reddi, H. V., McIver, B., Grebe, S. K., & Eberhardt, N. L. (2007). The paired box-8/ peroxisome proliferator-activated receptor-gamma oncogene in thyroid tumor- igenesis. Endocrinology 148(3), 932-935.

Reincke, M., Karl, M., Travis, W. H., Mastorakos, G., Allolio, B., Linehan, H. M., et al. (1994). p53 mutations in human adrenocortical neoplasms: immunohistochemical and molecular studies. J Clin Endocrinol Metab 78(3), 790-794.

Ringel, M. D., Hayre, N., Saito, J., Saunier, B., Schuppert, F., Burch, H., et al. (2001). Overexpression and overactivation of Akt in thyroid carcinoma. Cancer Res 61(16), 6105-6111.

Robbins, R. J., Tuttle, R. M., Sharaf, R. N., Larson, S. M., Robbins, H. K., Ghossein, R. A., et al. (2001). Preparation by recombinant human thyrotropin or thyroid hormone withdrawal are comparable for the detection of residual differentiated thyroid carcinoma. J Clin Endocrinol Metab 86(2), 619-625.

Rochaix, P., Monteil-Onteniente, S., Rochette-Egly, C., Caratero, C., Voigt, J. J., & Jozan, S. (1998). Reduced expression of retinoic acid receptor beta protein (RAR beta) in human papillary thyroid carcinoma: immunohistochemical and western blot study. Histopathology 33(4), 337-343.

Rodgers, S., & Perrier, N. (2006). Parathyroid carcinoma. Curr Opin Oncol 18(1), 16-22. Romei, C., Ciampi, R., Faviana, P., Agate, L., Molinaro, E., Bottici, V., et al. (2008). BRAFV600E mutation, but not RET/PTC rearrangements, is correlated with a lower expression of both thyroperoxidase and sodium iodide symporter genes in papillary thyroid cancer. Endocr Relat Cancer 15(2), 511-520.

Ronchi, C., Sbiera, S., Kraus, L., Wortmann, S., Johanssen, S., Adam, P., et al. in press. Expression of excision repair cross complementing group 1 and prognosis in adrenocortical carcinoma patients treated with platinum-based chemotherapy. Endocr Relat Cancer Feb 24 [Electronic publication ahead of print]. doi:10.1677/ERC-08-0224.

Ronga, G., Filesi, M., Montesano, T., Di Nicola, A. D., Pace, C., Travascio, L., et al. (2004). Lung metastases from differentiated thyroid carcinoma. A 40 years’ experience. QJ Nucl Med Mol Imaging 48(1), 12-19.

Rose, B., Matthay, K. K., Price, D., Huberty, J., Klencke, B., Norton, J. A., et al. (2003). High- dose 131I-metaiodobenzylguanidine therapy for 12 patients with malignant pheochromocytoma. Cancer 98(2), 239-248.

Rosen, L. S., Kurzrock, R., Mulay, M., Van Vugt, A., Purdom, M., Ng, C., et al. (2007). Safety, pharmacokinetics, and efficacy of AMG 706, an oral multikinase inhibitor, in patients with advanced solid tumors. J Clin Oncol 25(17), 2369-2376.

Rubin, M. R., Bilezikian, J. P., Birken, S., & Silverberg, S.J. (2008). Human chorionic gonadotropin measurements in parathyroid carcinoma. Eur J Endocrinol 159(4), 469-474.

Ruegemer, J. J., Hay, I. D., Bergstralh, E. J., Ryan, J. J., Offord, K. P., & Gorman, C. A. (1988). Distant metastases in differentiated thyroid carcinoma: a multivariate analysis of prognostic variables. J Clin Endocrinol Metab 67(3), 501-508.

Rugo, H. S., Herbst, R. S., Liu, G., Park, J. W., Kies, M. S., Steinfeldt, H. M., et al. (2005). Phase I trial of the oral antiangiogenesis agent AG-013736 in patients with advanced solid tumors: pharmacokinetic and clinical results. J Clin Oncol 23(24), 5474-5483.

Saeger, W., Fassnacht, M., Reincke, M., & Allolio, B. (2002). Expression of HER-2/neu receptor protein in adrenal tumors. Pathol Res Pract 198(7), 445-448.

Sakorafas, G. H., Friess, H., & Peros, G. (2008). The genetic basis of hereditary medullary thyroid cancer: clinical implications for the surgeon, with a particular emphasis on the role of prophylactic thyroidectomy. Endocr Relat Cancer 15(4), 871-884.

Salgia, R., Sherman, S., Hong, D. S., Ng, C. S., Frye, J., Janisch, L., et al. (2008). A phase I study of XL184, a RET, VEGFR2, and MET kinase inhibitor, in patients (pts) with advanced malignancies, including pts with medullary thyroid cancer (MTC). J Clin Oncol 26 Suppl; abstr 3522.

Salmenkivi, K., Arola, J., Voutilainen, R., Ilvesmaki, V., Haglund, C., Kahri, A. I., et al. (2001). Inhibin/activin betaB-subunit expression in pheochromocytomas favors benign diagnosis. J Clin Endocrinol Metab 86(5), 2231-2235.

Salmenkivi, K., Heikkila, P., Liu, J., Haglund, C., & Arola, J. (2003). VEGF in 105 pheochromocytomas: enhanced expression correlates with malignant outcome. Apmis 111(4), 458-464.

Samnotra, V., Vassilopoulou-Sellin, R., & Fojo, A. T. (2007). A phase II trial of gefitinib monotherapy in patients with unresectable adrenocortical carcinoma (ACC). J Clin Oncol suppl. abstr. 15527.

Santarpia, L., El-Naggar, A. K., Cote, G. J., Myers, J. N., & Sherman, S. I. (2008). Phosphatidylinositol 3-kinase/Akt and ras/raf-mitogen-activated protein kinase pathway mutations in anaplastic thyroid cancer. J Clin Endocrinol Metab 93(1), 278-284.

Santoro, M., Carlomagno, F., Romano, A., Bottaro, D. P., Dathan, N. A., Grieco, M., et al. (1995). Activation of RET as a dominant transforming gene by germline mutations of MEN2A and MEN2B. Science 267(5196), 381-383.

Santoro, M., Melillo, R. M., Carlomagno, F., Vecchio, G., & Fusco, A. (2004). Minireview: RET: normal and abnormal functions. Endocrinology 145(12), 5448-5451.

Sasano, H., Suzuki, T., Shizawa, S., Kato, K., & Nagura, H. (1994). Transforming growth factor alpha, epidermal growth factor, and epidermal growth factor receptor expression in normal and diseased human adrenal cortex by immunohistochem- istry and in situ hybridization. Mod Pathol 7(7), 741-746.

Sbiera, S., Wortmann, S., & Fassnacht, M. (2008). Dendritic cell based immunotherapy - a promising therapeutic approach for endocrine malignancies. Horm Metab Res 40(2), 89-98.

Schlumberger, M., Carlomagno, F., Baudin, E., Bidart, J. M., & Santoro, M. (2008). New therapeutic approaches to treat medullary thyroid carcinoma. Nat Clin Pract Endocrinol Metab 4(1), 22-32.

Schlumberger, M. J., Elisei, R., Sherman, S. I., et al. (2007). Phase 2 trial of motesanib diphosphate(AMG706) in patients with medullary thyroid cancer (MTC). Abstracts from the 89th annual meeting of the Endocrine Society (ENDO 07), Toronto.

Schmutzler, C., Brtko, J., Bienert, K., & Kohrle, J. (1996). Effects of retinoids and role of retinoic acid receptors in human thyroid carcinomas and cell lines derived therefrom. Exp Clin Endocrinol Diabetes 104(Suppl 4), 16-19.

Schmutzler, C., Winzer, R., Meissner-Weigl, J., & Kohrle, J. (1997). Retinoic acid increases sodium/iodide symporter mRNA levels in human thyroid cancer cell lines and

suppresses expression of functional symporter in nontransformed FRTL-5 rat thyroid cells. Biochem Biophys Res Commun 240(3), 832-838.

Scholz, T., Eisenhofer, G., Pacak, K., Dralle, H., & Lehnert, H. (2007). Clinical review: current treatment of malignant pheochromocytoma. J Clin Endocrinol Metab 92(4), 1217-1225.

Schott, M., Feldkamp, J., Klucken, M., Kobbe, G., Scherbaum, W. A., & Seissler, J. (2002). Calcitonin-specific antitumor immunity in medullary thyroid carcinoma following dendritic cell vaccination. Cancer Immunol Immunother 51(11-12), 663-668.

Schott, M., Feldkamp, J., Schattenberg, D., Krueger, T., Dotzenrath, C., Seissler, J., et al. (2000). Induction of cellular immunity in a parathyroid carcinoma treated with tumor lysate-pulsed dendritic cells. Eur J Endocrinol 142(3), 300-306.

Schott, M., Seissler, J., Lettmann, M., Fouxon, V., Scherbaum, W. A., & Feldkamp, J. (2001). Immunotherapy for medullary thyroid carcinoma by dendritic cell vaccination. J Clin Endocrinol Metab 86(10), 4965-4969.

Schreck, R., Schnieders, F., Schmutzler, C., & Kohrle, J. (1994). Retinoids stimulate type I iodothyronine 5’-deiodinase activity in human follicular thyroid carcinoma cell lines. J Clin Endocrinol Metab 79(3), 791-798.

Schteingart, D. E., Doherty, G. M., Gauger, P. G., Giordano, T. J., Hammer, G. D., Korobkin, M., et al. (2005). Management of patients with adrenal cancer: recommendations of an international consensus conference. Endocr Relat Cancer 12(3), 667-680.

Schwartz, D. L., Rana, V., Shaw, S., Yazbeck, C., Ang, K. K., Morrison, W. H., et al. (2008). Postoperative radiotherapy for advanced medullary thyroid cancer - local disease control in the modern era. Head Neck 30(7), 883-888.

Shane, E. (2001). Clinical review 122: parathyroid carcinoma. J Clin Endocrinol Metab 86(2), 485-493.

Shattuck, T. M., Välimäki, S., Obara, T., Gaz, R. D., Clark, O. H., Shoback, D., et al. (2003). Somatic and germ-line mutations of the HRPT2 gene in sporadic parathyroid carcinoma. N Engl J Med 349(18), 1722-1729.

Sherman, S. I. (2003). Thyroid carcinoma. Lancet 361(9356), 501-511.

Sherman, S. I. (2008). Early clinical studies of novel therapies for thyroid cancers. En- docrinol Metab Clin North Am 37(2), 511-524 xi.

Sherman, S. I., Tielens, E. T., Sostre, S., Wharam, M. D., Jr., & Ladenson, P. W. (1994). Clinical utility of posttreatment radioiodine scans in the management of patients with thyroid carcinoma. J Clin Endocrinol Metab 78(3), 629-634.

Sherman, S. I., Wirth, L. J., Droz, J. P., Hofmann, M., Bastholt, L., Martins, R. G., et al. (2008). Motesanib diphosphate in progressive differentiated thyroid cancer. N Engl J Med 359(1), 31-42.

Shimaoka, K., Schoenfeld, D. A., DeWys, W. D., Creech, R. H., & DeConti, R. (1985). A randomized trial of doxorubicin versus doxorubicin plus cisplatin in patients with advanced thyroid carcinoma. Cancer 56(9), 2155-2160.

Short, S. C., Suovuori, A., Cook, G., Vivian, G., & Harmer, C. (2004). A phase II study using retinoids as redifferentiation agents to increase iodine uptake in metastatic thyroid cancer. Clin Oncol (R Coll Radiol) 16(8), 569-574.

Shoup, M., Stojadinovic, A., Nissan, A., Ghossein, R. A., Freedman, S., Brennan, M. F., et al. (2003). Prognostic indicators of outcomes in patients with distant metastases from differentiated thyroid carcinoma. J Am Coll Surg 197(2), 191-197.

Sidhu, S., Marsh, D. J., Theodosopoulos, G., Philips, J., Bambach, C. P., Campbell, P., et al. (2002). Comparative genomic hybridization analysis of adrenocortical tumors. J Clin Endocrinol Metab 87(7), 3467-3474.

Simon, D., Korber, C., Krausch, M., Segering, J., Groth, P., Gorges, R., et al. (2002). Clinical impact of retinoids in redifferentiation therapy of advanced thyroid cancer: final results of a pilot study. Eur J Nucl Med Mol Imaging 29(6), 775-782.

Soh, E. Y., Duh, Q. Y., Sobhi, S. A., Young, D. M., Epstein, H. D., Wong, M. G., et al. (1997). Vascular endothelial growth factor expression is higher in differentiated thyroid cancer than in normal or benign thyroid. J Clin Endocrinol Metab 82(11), 3741-3747. Song, J. H., Chaudhry, F. S., & Mayo-Smith, W. W. (2008). The incidental adrenal mass on CT: prevalence of adrenal disease in 1,049 consecutive adrenal masses in patients with no known malignancy. AJR Am J Roentgenol 190(5), 1163-1168.

Soon, P. S., McDonald, K. L., Robinson, B. G., & Sidhu, S. B. (2008). Molecular markers and the pathogenesis of adrenocortical cancer. Oncologist 13(5), 548-561.

Sosa, J. A., & Udelsman, R. (2006). Papillary thyroid cancer. Surg Oncol Clin N Am 15(3), 585-601.

Specht, M. C., Tucker, O. N., Hocever, M., Gonzalez, D., Teng, L., & Fahey, T. J., III (2002). Cyclooxygenase-2 expression in thyroid nodules. J Clin Endocrinol Metab 87(1), 358-363.

Stambolic, V., Tsao, M. S., Macpherson, D., Suzuki, A., Chapman, W. B., & Mak, T. W. (2000). High incidence of breast and endometrial neoplasia resembling human Cowden syndrome in pten+/- mice. Cancer Res 60(13), 3605-3611.

Stephan, E. A., Chung, T. H., Grant, C. S., Kim, S., Von Hoff, D. D., Trent, J. M., et al. (2008). Adrenocortical carcinoma survival rates correlated to genomic copy number variants. Mol Cancer Ther 7(2), 425-431.

Strahl, B. D., & Allis, C. D. (2000). The language of covalent histone modifications. Nature 403(6765), 41-45.

Strock, C. J., Park, J. I., Rosen, M., Dionne, C., Ruggeri, B., Jones-Bolin, S., et al. (2003). CEP- 701 and CEP-751 inhibit constitutively activated RET tyrosine kinase activity and block medullary thyroid carcinoma cell growth. Cancer Res 63(17), 5559-5563.

Strong, V. E., Kennedy, T., Al-Ahmadie, H., Tang, L., Coleman, J., Fong, Y., et al. (2008). Prognostic indicators of malignancy in adrenal pheochromocytomas: clinical, histo- pathologic, and cell cycle/apoptosis gene expression analysis. Surgery 143(6), 759-768. Sugg, S. L., Ezzat, S., Rosen, I. B., Freeman, J. L., & Asa, S. L. (1998). Distinct multiple RET/ PTC gene rearrangements in multifocal papillary thyroid neoplasia. J Clin Endocrinol Metab 83(11), 4116-4122.

Sugino, K., Ito, K., Mimura, T., Nagahama, M., Fukunari, N., Kubo, A., et al. (2002). The important role of operations in the management of anaplastic thyroid carcinoma. Surgery 131(3), 245-248.

Sun, Y. (2006). p53 and its downstream proteins as molecular targets of cancer. Mol Carcinog 45(6), 409-415.

Tadjine, M., Lampron, A., Ouadi, L., & Bourdeau, I. (2008). Frequent mutations of beta- catenin gene in sporadic secreting adrenocortical adenomas. Clin Endocrinol (Oxf) 68(2), 264-270.

Tadjine, M., Lampron, A., Ouadi, L., Horvath, A., Stratakis, C. A., & Bourdeau, I. (2008). Detection of somatic beta-catenin mutations in primary pigmented nodular adrenocortical disease (PPNAD). Clin Endocrinol (Oxf) 69(3), 367-373.

Takekoshi, K., Isobe, K., Yashiro, T., Hara, H., Ishii, K., Kawakami, Y., et al. (2004). Expression of vascular endothelial growth factor (VEGF) and its cognate receptors in human pheochromocytomas. Life Sci 74(7), 863-871.

Takiyama, Y., Miyokawa, N., Sugawara, A., Kato, S., Ito, K., Sato, K., et al. (2004). Decreased expression of retinoid X receptor isoforms in human thyroid carcinomas. J Clin Endocrinol Metab 89(11), 5851-5861.

Tennvall, J., Lundell, G., Wahlberg, P., Bergenfelz, A., Grimelius, L., Akerman, M., et al. (2002). Anaplastic thyroid carcinoma: three protocols combining doxorubicin, hyperfractionated radiotherapy and surgery. Br J Cancer 86(12), 1848-1853.

Tepmongkol, S., Keelawat, S., Honsawek, S., & Ruangvejvorachai, P. (2008). Rosiglita- zone effect on radioiodine uptake in thyroid carcinoma patients with high thyroglobulin but negative total body scan: a correlation with the expression of peroxisome proliferator-activated receptor-gamma. Thyroid 18(7), 697-704.

Terzolo, M., Angeli, A., Fassnacht, M., Daffara, F., Tauchmanova, L., Conton, P. A., et al. (2007). Adjuvant mitotane treatment in patients with adrenocortical carcinoma. N Engl J Med 356(23), 372-380.

Teunissen, J. J., Kwekkeboom, D. J., & Krenning, E. P. (2006). Staging and treatment of differentiated thyroid carcinoma with radiolabeled somatostatin analogs. Trends Endocrinol Metab 17(1), 19-25.

Thiagalingam, S., Cheng, K. H., Lee, H. J., Mineva, N., Thiagalingam, A., & Ponte, J. F. (2003). Histone deacetylases: unique players in shaping the epigenetic histone code. Ann N Y Acad Sci 983, 84-100.

Thouennon, E., Elkahloun, A. G., Guillemot, J., Gimenez-Roqueplo, A. P., Bertherat, J., Pierre, A., et al. (2007). Identification of potential gene markers and insights into the pathophysiology of pheochromocytoma malignancy. J Clin Endocrinol Metab 92(12), 4865-4872.

Tominaga, Y., Tsuzuki, T., Matsuoka, S., Uno, N., Sato, T., Shimabukuro, S., et al. (2008). Expression of parafibromin in distant metastatic parathyroid tumors in patients with advanced secondary hyperparathyroidism due to chronic kidney disease. World J Surg 32(5), 815-821.

Tontonoz, P., Singer, S., Forman, B. M., Sarraf, P., Fletcher, J. A., Fletcher, C. D., et al. (1997). Terminal differentiation of human liposarcoma cells induced by ligands for peroxisome proliferator-activated receptor gamma and the retinoid X receptor. Proc Natl Acad Sci U S A 94(1), 237-241.

Troncone, L., & Rufini, V. (1997). 131I-MIBG therapy of neural crest tumours (review). Anticancer Res 17(3B), 1823-1831.

Trovisco, V., Soares, P., & Sobrinho-Simoes, M. (2006). B-RAF mutations in the etiopathogen- esis, diagnosis, and prognosis of thyroid carcinomas. Hum Pathol 37(7), 781-786.

Tuttle, R. M., Fleisher, M., Francis, G. L., & Robbins, R. J. (2002). Serum vascular endo- thelial growth factor levels are elevated in metastatic differentiated thyroid cancer but not increased by short-term TSH stimulation. J Clin Endocrinol Metab 87(4), 1737-1742.

Unger, N., Serdiuk, I., Sheu, S. Y., Walz, M. K., Schulz, S., Saeger, W., et al. (2008). Immunohistochemical localization of somatostatin receptor subtypes in benign and malignant adrenal tumours. Clin Endocrinol (Oxf) 68(6), 850-857.

Valkema, R., De Jong, M., Bakker, W. H., Breeman, W. A., Kooij, P. P., Lugtenburg, P. J., et al. (2002). Phase I study of peptide receptor radionuclide therapy with [In-DTPA] octreotide: the Rotterdam experience. Semin Nucl Med 32(2), 110-122.

Vamecq, J., & Latruffe, N. (1999). Medical significance of peroxisome proliferator- activated receptors. Lancet 354(9173), 141-148.

Van Herle, A. J., Agatep, M. L., Padua, D. N., III, Totanes, T. L., Canlapan, D. V., Van Herle, H. M., et al. (1990). Effects of 13 cis-retinoic acid on growth and differentiation of human follicular carcinoma cells (UCLA R0 82 W-1) in vitro. J Clin Endocrinol Metab 71(3), 755-763.

van Nederveen, F. H., Perren, A., Dannenberg, H., Petri, B. J., Dinjens, W. N., Komminoth, P., et al. (2006). PTEN gene loss, but not mutation, in benign and malignant phaeochromocytomas. J Pathol 209(2), 274-280.

van Veelen, W., van Gasteren, C. J., Acton, D. S., Franklin, D. S., Berger, R., Lips, C. J., et al. (2008). Synergistic effect of oncogenic RET and loss of p18 on medullary thyroid carcinoma development. Cancer Res 68(5), 1329-1337.

Varley, J. M., McGown, G., Thorncroft, M., James, L. A., Margison, G. P., Forster, G., et al. (1999). Are there low-penetrance TP53 alleles? Evidence from childhood adrenocortical tumors. Am J Hum Genet 65(4), 995-1006.

Vasef, M. A., Brynes, R. K., Sturm, M., Bromley, C., & Robinson, R. A. (1999). Expression of cyclin D1 in parathyroid carcinomas, adenomas, and hyperplasias: a paraffin immunohistochemical study. Mod Pathol 12(4), 412-416.

Vasko, V., Ferrand, M., Di Cristofaro, J., Carayon, P., Henry, J. F., & de Micco, C. (2003). Specific pattern of RAS oncogene mutations in follicular thyroid tumors. J Clin Endocrinol Metab 88(6), 2745-2752.

Vasko, V., Saji, M., Hardy, E., Kruhlak, M., Larin, A., Savchenko, V., et al. (2004). Akt activation and localisation correlate with tumour invasion and oncogene expres- sion in thyroid cancer. J Med Genet 41(3), 161-170.

Vini, L., & Harmer, C. (2002). Management of thyroid cancer. Lancet Oncol 3(7), 407-414. Wakeling, A. E., Guy, S. P., Woodburn, J. R., Ashton, S. E., Curry, B. J., Barker, A. J., et al. (2002). ZD1839 (Iressa): an orally active inhibitor of epidermal growth factor signaling with potential for cancer therapy. Cancer Res 62(20), 5749-5754.

Waldherr, C., Schumacher, T., Pless, M., Crazzolara, A., Maecke, H. R., Nitzsche, E. U., et al. (2001). Radiopeptide transmitted internal irradiation of non-iodophil thyroid cancer and conventionally untreatable medullary thyroid cancer using. Nucl Med Commun 22(6), 673-678.

Wang, Y., Hou, P., Yu, H., Wang, W., Ji, M., Zhao, S., et al. (2007). High prevalence and mutual exclusivity of genetic alterations in the phosphatidylinositol-3-kinase/akt pathway in thyroid tumors. J Clin Endocrinol Metab 92(6), 2387-2390.

Watanabe, K., Hiraki, H., Hasegawa, H., Tanigawa, T., Emura, I., Honma, K., et al. (1997). Immunohistochemical localization of endothelin-1, endothelin-3 and endothelin receptors in human pheochromocytoma and paraganglioma. Pathol Int 47(8), 540-546. Weber, M. M., Auernhammer, C. J., Kiess, W., & Engelhardt, D. (1997). Insulin-like growth factor receptors in normal and tumorous adult human adrenocortical glands. Eur J Endocrinol 136(3), 296-303.

Wedge, S. R., Ogilvie, D. J., Dukes, M., Kendrew, J., Chester, R., Jackson, J. A., et al. (2002). ZD6474 inhibits vascular endothelial growth factor signaling, angiogenesis, and tumor growth following oral administration. Cancer Res 62(16), 4645-4655. Weiner, L. M. (2008). Cancer immunotherapy - the endgame begins. N Engl J Med 358(25), 2664-2665.

Wells, S. A., Jr., Gosnell, J., Gagel, R., Moley, J. F., Pfister, D., Sosa, J. A., et al. (2007). Vandetanib in metastatic hereditary medullary thyroid cancer: follow-up results of an open-label Phase II trial. J Clin Oncol suppl; abstr. 6018.

Widakowich, C., de Castro, G., Jr., de Azambuja, E., Dinh, P., & Awada, A. (2007). Review: side effects of approved molecular targeted therapies in solid cancers. Oncologist 12(12), 1443-1455.

Wilhelm, S. M., Carter, C., Tang, L., Wilkie, D., McNabola, A., Rong, H., et al. (2004). BAY 43-9006 exhibits broad spectrum oral antitumor activity and targets the RAF/MEK/ ERK pathway and receptor tyrosine kinases involved in tumor progression and angiogenesis. Cancer Res 64(19), 7099-7109.

Wiseman, S. M., Griffith, O. L., Deen, S., Rajput, A., Masoudi, H., Gilks, B., et al. (2007). Identification of molecular markers altered during transformation of differentiated into anaplastic thyroid carcinoma. Arch Surg 142(8), 717-727 discussion 727-9.

Wiseman, S. M., Griffith, O. L., Melck, A., Masoudi, H., Gown, A., Nabi, I. R., et al. (2008). Evaluation of type 1 growth factor receptor family expression in benign and malignant thyroid lesions. Am J Surg 195(5), 667-673 discussion 673.

Wiseman, S. M., Masoudi, H., Niblock, P., Turbin, D., Rajput, A., Hay, J., et al. (2006). Derangement of the E-cadherin/catenin complex is involved in transformation of differentiated to anaplastic thyroid carcinoma. Am J Surg 191(5), 581-587.

Woodard, G. E., Lin, L., Zhang, J. H., Agarwal, S. K., Marx, S. J., & Simonds, W. F. (2005). Parafibromin, product of the hyperparathyroidism-jaw tumor syndrome gene HRPT2, regulates cyclin D1/PRAD1 expression. Oncogene 24(7), 1272-1276.

Wortmann, S., Quinkler, M., Ritter, C., Hahner, S., Johanssen, S., Allolio, B., et al. (2009). Bevacizumab combined with capecitabine in advanced adrenocortical carcinoma. Exp Clin Diab Endocrinol (abstract German Endocrine Society meeting) 117, OP5-5. Woyach, J. A., Kloos, R. T., Ringel, M. D., Arbogast, D., Collamore, M., Zwiebel,J.A., et al. (2008). Lack of therapeutic effect of the histone deacetylase inhibitor vorinostat in patients with metastatic radioiodine-refractory thyroid carcinoma. J Clin Endocrinol Metab.

Wu, L. T., Averbuch, S. D., Ball, D. W., de Bustros, A., Baylin, S. B., & McGuire, W. P., III (1994). Treatment of advanced medullary thyroid carcinoma with a combination of cyclophosphamide, vincristine, and dacarbazine. Cancer 73(2), 432-436.

Wynne, A. G., van Heerden, J., Carney, J. A., & Fitzpatrick, L. A. (1992). Parathyroid carcinoma: clinical and pathologic features in 43 patients. Medicine (Baltimore) 71(4), 197-205.

Xing, M. (2005). BRAF mutation in thyroid cancer. Endocr Relat Cancer 12(2), 245-262. Yamamoto, S., Tomita, Y., Uruno, T., Hoshida, Y., Qiu, Y., Iizuka, N., et al. (2005). Increased expression of valosin-containing protein (p97) is correlated with disease recurrence in follicular thyroid cancer. Ann Surg Oncol 12(11), 925-934.

Ye, L., Santarpia, L., Cote, G. J., El-Naggar, A. K., & Gagel, R. F. (2008). High resolution array-comparative genomic hybridization profiling reveals deoxyribonucleic acid copy number alterations associated with medullary thyroid carcinoma. J Clin Endocrinol Metab 93(11), 4367-4372.

Yeh, M. W., Rougier, J. P., Park, J. W., Duh, Q, Y., Wong, M., Werb, Z., et al. (2006). Differentiated thyroid cancer cell invasion is regulated through epidermal growth factor receptor-dependent activation of matrix metalloproteinase (MMP)-2/ gelatinase A. Endocr Relat Cancer 13(4), 1173-1183.

You, M. J., Castrillon, D. H., Bastian, B. C., O’Hagan, R. C., Bosenberg, M. W., Parsons, R., et al. (2002). Genetic analysis of Pten and Ink4a/Arf interactions in the suppression of tumorigenesis in mice. Proc Natl Acad Sci U S A 99(3), 1455-1460.

You, Y. N., & Wells, S. A., Jr. (2007). Role of surgeons in clinical trials for thyroid cancer. World J Surg 31(5), 987-995.

Yu, X. M., Lo, C. Y., Chan, W. F., Lam, K. Y., Leung, P., & Luk, J. M. (2005). Increased expression of vascular endothelial growth factor C in papillary thyroid carcinoma correlates with cervical lymph node metastases. Clin Cancer Res 11(22), 8063-8069.

Zacharieva, S., Atanassova, I., Orbetzova, M., Nachev, E., Kalinov, K., Kirilov, G., et al. (2004). Circulating vascular endothelial growth factor and active renin concentra- tions and prostaglandin E2 urinary excretion in patients with adrenal tumours. Eur J Endocrinol 150(3), 345-349.

Zatelli, M. C., Piccin, D., Tagliati, F., Bottoni, A., Luchin, A., Vignali, C., et al. (2006). Selective activation of somatostatin receptor subtypes differentially modulates secretion and viability in human medullary thyroid carcinoma primary cultures: potential clinical perspectives. J Clin Endocrinol Metab 91(6), 2218-2224.

Zhao, J., Speel, E. J., Muletta-Feurer, S., Rutimann, K., Saremaslani, P., Roth, J., et al. (1999). Analysis of genomic alterations in sporadic adrenocortical lesions. Gain of chromo- some 17 is an early event in adrenocortical tumorigenesis. Am J Pathol 155(4), 1039-1045.

Zielke, A., Middeke, M., Hoffmann, S., Colombo-Benkmann, M., Barth, P., Hassan, I., et al. (2002). VEGF-mediated angiogenesis of human pheochromocytomas is associated to malignancy and inhibited by anti-VEGF antibodies in experimental tumors. Surgery 132(6), 1056-1063 discussion 1063.

Zimmermann, S., & Martens, U. M. (2007). Telomeres and telomerase as targets for cancer therapy. Cell Mol Life Sci 64(7-8), 906-921.