A randomized trial of a single-dose rasburicase versus five-daily doses in patients at risk for tumor lysis syndrome.

BACKGROUND: Tumor lysis syndrome (TLS) is a life-threatening disorder characterized by hyperuricemia and metabolic derangements. The efficacy of rasburicase, administered daily for 5 days, has been well established. However, the optimal duration of therapy is unknown in adults. PATIENTS AND METHODS: We evaluated the efficacy of rasburicase (0.15 mg/kg) administered as single dose followed by as needed dosing (maximum five doses) versus daily dosing for 5 days in adult patients at risk for TLS. RESULTS: Eighty of the 82 patients enrolled received rasburicase; 40 high risk [median uric acid (UA) 8.5 mg/dl; range, 1.5-19.7] and 40 potential risk (UA = 5.6 mg/dl; range, 2.4-7.4). Seventy-nine patients (99%) experienced normalization in their UA within 4 h after the first dose; 84% to an undetectable level (<0.7 mg/dl). Thirty-nine of 40 (98%) patients in the daily-dose arm and 34 of 40 (85%) patients in single-dose arm showed sustained UA response. Six high-risk patients within the single-dose arm required second dose for UA >7.5 mg/dl. Rasburicase was well tolerated; one patient with glucose-6-phosphate dehydrogenase deficiency developed methemoglobinemia and hemolysis. CONCLUSIONS: Rasburicase is highly effective for prevention and management of hyperuricemia in adults at risk for TLS. Single-dose rasburicase was effective in most patients; only a subset of high-risk patients required a second dose.

Survival and human papillomavirus in oropharynx cancer in TAX 324: a subset analysis from an international phase III trial.

BACKGROUND: The association between human papillomavirus (HPV) and overall survival (OS) in oropharynx cancer (OPC) was retrospectively examined in TAX 324, a phase III trial of sequential therapy for locally advanced head and neck cancer. METHODS: Accrual for TAX 324 was completed in 2003 and data updated through 2008. Pretherapy tumor biopsies were studied by PCR for human papillomavirus type 16 and linked to OS, progression-free survival (PFS) and demographics. RESULTS: Of 264 patients with OPC, 111 (42%) had evaluable biopsies; 56 (50%) were HPV+ and 55 (50%) were HPV-. HPV+ patients were significantly younger (54 versus 58 years, P = 0.02), had T1/T2 primary cancers (49% versus 20%, P = 0.001), and had a performance status of zero (77% versus 49%, P = 0.003). OS and PFS were better for HPV+ patients (OS, hazard ratio = 0.20, P < 0.0001). Local-regional failure was less in HPV+ patients (13% versus 42%, P = 0.0006); at 5 years, 82% of HPV+ patients were alive compared with 35% of HPV- patients (P < 0.0001). CONCLUSIONS: HPV+ OPC has a different biology compared with HPV- OPC; 5-year OS, PFS, and local-regional control are unprecedented. These results support the possibility of selectively reducing therapy and long-term morbidity in HPV+ OPC while preserving survival and approaching HPV- disease with more aggressive treatment.

Hypercalcemia in cancer patients: pathobiology and management.

Hypercalcemia is the most common life-threatening metabolic disorder associated with cancer, occurring in approximately 10-30% of all patients with neoplastic disease, although it occurs much less often in the pediatric setting. Hypercalcemia can emerge in hematologic malignancies, particularly multiple myeloma, as well as assorted solid tumors, primarily lung and breast cancers, and can even dominate the clinical picture in select patients. Early diagnosis and treatment with fluids and drugs that lower calcium levels in the blood can improve symptoms in a few days, ameliorate the quality of life of these patients, and avoid delays in the implementation of further anticancer treatments. Occasionally, the symptoms of hypercalcemia can appear gradually, and may be non-specific, resembling symptoms of many cancers and other comorbidities, especially in the elderly, thus resulting in an underestimated incidence of hypercalcemia in cancer patients. Of note, there is an increasing number of antineoplastic compounds that can interfere with calcium metabolism. Taking into consideration both the severity of hypercalcemia and the tumor status, health care providers should determine and apply appropriate treatment measures. We provide a comprehensive subjective synthesis of peer-reviewed evidence on the pathophysiology and treatment of hypercalcemia in cancer patients.

Hormonal effects on drug metabolism through the CYP system: perspectives on their potential significance in the era of pharmacogenomics.

Cytochrome P450 (CYP) is a group of enzymes that metabolize drugs to a more water-soluble form, rendering them available for renal excretion. The major site of CYP expression is the liver. Nearly 50% of all medications currently on the market are metabolized by the enzyme CYP3A4, while metabolism of another 35-40% occurs through enzymes CYP1A2, CYP2C19, CYP2D6, CYP3A5 CYP3A6, and CYP3A7. Here, we summarize the current knowledge of the effects of hormones on the CYP family. The term "hormone" is used in its broad sense and includes products of the major endocrine glands (i.e., thyroid, adrenals, gonads, pancreas) and compounds that are not classically considered hormones, such as neurogenic amines, cytokines, interleukins, and eicosanoids. In addition, we comment on the effects on CYP expression of states associated with profound hormonal changes, such as pregnancy, malnutrition, obesity, diabetes mellitus, systemic inflammation, and conditions of altered extracellular fluid volume or osmolality. Available data are limited and are derived primarily from in vitro and animal studies. Moreover, the picture is obscured by conflicting results among studies and the complexity of the regulation of the expression and activity of elements of the CYP system. While the clinical significance of hormonal effects on the CYP system remains to be determined, we anticipate that such effects will be most pertinent to drugs with a narrow therapeutic range. Further research is needed to determine the scope and significance of these effects in view of rapid advances in the field of pharmacogenomics and the ever-increasing number of drugs available for therapeutic use.

Molecular elements of apoptosis-regulating pathways in follicular thyroid cells: mining for novel therapeutic targets in the treatment of thyroid carcinoma.

Apoptosis or programmed cell death occurs in both normal and pathological conditions, including cancer. Dysregulation of apoptosis allows transformed cells to continually and uninhibitedly enter the cell cycle, thus perpetuating the sequence of mutation, genomic instability and, finally, oncogenesis. The cell death machinery includes cell surface receptors, adaptor molecules, proteolytic enzymes, such as caspases, and a variety of mitochondrial proteins, which interact with each other in a complex fashion. In addition, extensive "cross-talk" exists between the apoptotic pathways and several other signaling systems that govern growth and differentiation. Recent advances in molecular techniques have shed light upon elements of the above pathways in assorted malignancies, including non-medullary thyroid carcinoma (ThyrCa). A subgroup of ThyrCa patients is (or becomes over time) refractory to standard treatment modalities and eventually succumbs to their disease. For such patients with clinically aggressive ThyrCa, novel therapeutic agents are urgently needed. Changes in the sensitivity of cells to apoptosis have clear implications for the treatment of any malignancy. In this review, we outline the main molecular targets that play a role in apoptosis in ThyrCa cells, and discuss various options for promoting apoptosis, either by pharmacologic or gene transfer therapeutic interventions.

Resistance to thyroid hormone in a patient without thyroid hormone receptor mutations.

Resistance to thyroid hormone (RTH) is a clinical syndrome characterized by elevated serum thyroid hormone (TH) levels, unsuppressed thyrotropin (TSH) levels, and tissue hyposensitivity to TH. In almost all cases, the genetic basis of RTH lies in mutation of one of the two TH receptor beta (TRbeta) alleles. Recently, patients from several families with phenotypic manifestations of RTH in the absence of TR mutations have been described. We report a case of a 31-year-old woman who presented with goiter, tachycardia, elevated TH levels, unsuppressed TSH, and "inappropriately normal" levels of peripheral TH action markers. In two separate clinical evaluations, the patient exhibited typical clinical and biochemical evidence for peripheral and pituitary RTH. Surprisingly, reverse transcriptase-polymerase chain reaction (RT-PCR) of full-length TRalpha and TRbeta mRNAs, and genomic PCR using primers flanking exons encoding the carboxy-terminal region of TRbeta failed to demonstrate mutations in the TRalpha or TRbeta genes. It is likely that defects in the regulation of TR genes or mutations in transcriptional cofactors involved in TR signaling account for this patient's phenotype.

Somatic mutation of TRbeta can cause a defect in negative regulation of TSH in a TSH-secreting pituitary tumor.

In patients with TSH-secreting tumors (TSHomas), serum TSH is poorly suppressed by thyroid hormone. The mechanism for this defect in negative regulation of TSH secretion is not known. To investigate the possibility of a somatic mutation of TR causing this defect, we performed mutational analysis of TRbeta by RT-PCR using RNA obtained from five surgically resected TSHomas. In one TSHoma, we identified a somatic mutation in the ligand-binding domain of TRbeta that caused a His to Tyr substitution at codon 435 of TRbeta1 corresponding to codon 450 of TRbeta2. Interestingly, this mutation occurred in the same codon as two mutations (TRbetaH435L and H435Q) previously identified in patients with the syndrome of resistance to thyroid hormone. This mutant TRbeta had impaired T3 binding and T3-mediated negative regulation. It also blocked the negative regulation by wild-type TRbeta2 on glycoprotein hormone alpha-subunit and TSHbeta reporter genes in cotransfection studies. Our results demonstrate that somatic mutation of TRbeta occurred in a TSHoma and was probably responsible for the defect in negative regulation of TSH by thyroid hormone in the tumor.

The spectrum of thyroid diseases in childhood and its evolution during transition to adulthood: natural history, diagnosis, differential diagnosis and management.

In this contribution, we review current knowledge on the pathogenesis, diagnosis and differential diagnosis of thyroid disorders in childhood and adolescence, as well as present an update on therapy methods and management guidelines for these disorders. This overview is conceptually divided into two parts, one focusing on thyroid functional disorders, i.e. conditions leading to hyper- and hypothyroidism, and another one pertinent to structural abnormalities of the thyroid gland, i.e. nodular disorders and thyroid cancer. Currently, congenital hypothyroidism is diagnosed in a much more timely fashion rather than in the past, rendering hypothyroidism-related mental retardation and developmental deficits very rare in newborns and children and, hence, diminishing significantly its public health impact. At the same time, considerable advances have occurred in our understanding of the molecular basis of several genetic conditions affecting the thyroid gland in childhood, such as familial non-autoimmune hyperthyroidism, as well as of the pathways leading to thyroid neoplasia.

Renal metastases from thyroid papillary carcinoma: study of sodium iodide symporter expression.

Kidney metastases from thyroid cancer are rare. We report two such patients and demonstrate that the in vivo 131I uptake by the kidney metastasis is associated with high levels of sodium iodide (Na+/I-) symporter (NIS) expression in the first case. Case 1: A 61-year-old woman with papillary thyroid carcinoma-follicular variant (PTC-FV) presented with scapular metastasis. After thyroidectomy and scapulectomy, a 131I posttherapy scan showed left upper quadrant uptake. A 3.0-cm metastatic PTC-FV deposit was removed by partial nephrectomy. Case 2: A 53-year-old woman presented with back pain. A computed tomography (CT) scan showed a 3.5-cm renal mass, a multinodular goiter, and lung metastases thought secondary to a renal cell carcinoma. A unilateral nephrectomy revealed metastatic PTC-FV. After thyroidectomy, a 131I posttherapy scan showed lung and skeletal metastases. NIS immunoreactivity in tumoral tissue was strongly positive in the primary tumor, shoulder, and kidney metastasis in case 1, as well as in the primary tumor in case 2. Spotty, low-level NIS expression was observed in the kidney metastasis in case 2. In conclusion, kidney metastases of PTC-FV may occasionally retain adequate levels of NIS expression, enabling their detection during life. Thus, intense uptake in the abdomen during 131I imaging should not be assumed to be physiological gastrointestinal tract residual radionuclide activity.

Aberrant alternative splicing of thyroid hormone receptor in a TSH-secreting pituitary tumor is a mechanism for hormone resistance.

Patients with TSH-secreting pituitary tumors (TSHomas) have high serum TSH levels despite elevated thyroid hormone levels. The mechanism for this defect in the negative regulation of TSH secretion is not known. We performed RT-PCR to detect mutations in TRbeta from a surgically resected TSHoma. Analyses of the RT-PCR products revealed a 135-bp deletion within the sixth exon that encodes the ligand-binding domain of TRbeta2. This deletion was caused by alternative splicing of TRbeta2 mRNA, as near-consensus splice sequences were found at the junction site and no deletion or mutations were detected in the tumoral genomic DNA. This TRbeta variant (TRbeta2spl) lacked thyroid hormone binding and had impaired T3-dependent negative regulation of both TSHbeta and glycoprotein hormone alpha-subunit genes in cotransfection studies. Furthermore, TRbeta2spl showed dominant negative activity against the wild-type TRbeta2. These findings strongly suggest that aberrant alternative splicing of TRbeta2 mRNA generated an abnormal TR protein that accounted for the defective negative regulation of TSH in the TSHoma. This is the first example of aberrant alternative splicing of a nuclear hormone receptor causing hormonal dysregulation. This novel posttranscriptional mechanism for generating abnormal receptors may occur in other hormone-resistant states or tumors in which no receptor mutation is detected in genomic DNA.

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.

Thyroid carcinoma accounts for the majority of deaths from endocrine cancers. A major cause of treatment failure is the inability to trap iodine. Chemotherapeutic agents with differentiating properties have been tried in an attempt to increase iodine uptake. We examined the ability of the novel histone deacetylase (HDAC) inhibitor, depsipeptide (FR901228), to modulate the expression of thyroid-specific genes. Four cell lines, two derived from follicular thyroid carcinomas (FTC 133 and FTC 236) and two derived from anaplastic thyroid carcinomas (SW-1736 and KAT-4) were used. In these four cell lines, a very low concentration of depsipeptide (1 ng/mL) increased histone acetylation and expression of both thyroglobulin and the Na(+)/I(-) symporter messenger RNAs. After 3 days, messenger RNA levels approached those of a normal thyroid control. Depsipeptide induced increases in (125)I accumulation indicated that a functional Na(+)/I(-) symporter protein was induced. Transient transfections indicate that the effects are mediated at least in part by a trans-activating factor. These in vitro results suggest that depsipeptide or other histone deacetylase inhibitors might be used clinically in thyroid carcinomas that are unable to trap iodine as an adjunct to radioiodine therapy.

A case of spurious hypercalcitoninemia: a cautionary tale on the use of plasma calcitonin assays in the screening of patients with thyroid nodules for neoplasia.

The measurement of plasma CT has an important role as a screening test for medullary thyroid carcinoma (MTC) in patients with thyroid nodules. However, elevated plasma CT levels should be interpreted within the context of the overall clinical picture in each individual case and carefully validated before therapeutic decisions are made. We present the case of a 17-yr-old girl who was referred to us with a thyroid nodule and elevated plasma CT levels, as measured by a one-site RIA not involving prior plasma extraction. Plasma CT was re-measured using two different methods, a RIA with prior plasma extraction and a two-site immunochemiluminometric assay (ICMA), and was either very low or undetectable. Subsequently, samples were re-assayed using the initially applied CT RIA; plasma CT levels were again found to be elevated. These elevations were of a spurious nature, probably caused by the presence of an unidentified substance in the patient's plasma interfering with the measurement of CT in the initially used RIA. Our patient was eventually diagnosed with Hashimoto's thyroiditis, and had no evidence of MTC. As several conditions can cause either true or spurious hypercalcitoninemia, we suggest that elevated plasma CT levels should be confirmed at least once before other extensive diagnostic investigations are initiated or thyroidectomy is recommended. Finally, the assay selected should detect only the mature CT molecule.

Exaggerated levothyroxine malabsorption due to calcium carbonate supplementation in gastrointestinal disorders.

OBJECTIVE: To describe a patient with primary hypothyroidism in whom ingestion of levothyroxine with calcium carbonate led to markedly elevated serum thyrotropin concentrations. CASE SUMMARY: A 61-year-old white woman with primary hypothyroidism, systemic lupus erythematosus, celiac disease, and history of Whipple resection for pancreatic cancer was euthyroid with levothyroxine 175-188 micrograms/d. After taking a high dose of calcium carbonate (1250 mg three times daily) with levothyroxine, she developed biochemical evidence of hypothyroidism (thyrotropin up to 41.4 mU/L) while remaining clinically euthyroid. Delaying calcium carbonate administration by four hours returned her serum thyrotropin to a borderline high concentration (5.7 mU/L) within a month. Serum concentrations of unbound and total thyroxine and triiodothyronine tended to decrease, but remained borderline low to normal while the patient concomitantly received levothyroxine and calcium carbonate. DISCUSSION: Concomitant administration of levothyroxine and calcium carbonate often results in levothyroxine malabsorption. While in most patients the clinical consequences of this interaction, even with prolonged exposure, are relatively small, overt hypothyrodism may develop in patients with preexisting malabsorption disorders. However, as the current case illustrates, the clinical manifestations of the initial levothyroxine deficit may not always be apparent and, of all usual laboratory thyroid function tests, only thyrotropin measurement will reliably uncover the exaggerated levothyroxine malabsorption. CONCLUSIONS: Decreased absorption of levothyroxine when given with calcium carbonate may be particularly pronounced in patients with preexisting malabsorption disorders. Once recognized, a change in drug administration schedule usually minimizes or eliminates this interaction.

Effectiveness of long-acting octreotide in suppressing hormonogenesis and tumor growth in thyrotropin-secreting pituitary adenomas: report of two cases.

BACKGROUND: The subcutaneous (s.c.) administration of somatostatin analogs, such as octreotide acetate (SMS) and lanreotide, in patients with thyrotropin (TSH)-secreting pituitary adenomas (TSPA's)--thyrotropinomas with residual tumor after initial surgical therapy is effective in controlling hyperthyroidism, as well as curtailing tumor growth in the majority of patients. Long-acting preparations of the above agents, i.e. SMS-LAR and lanreotide-SR, have been synthesized and can be administered as depot injections intramuscularly (i.m.) at intervals of several weeks. Recent studies have reported on preliminary data regarding the use of such preparations in patients with TSPA's. MATERIALS AND METHODS: We present two cases of TSPA's with residual tumor following transsphenoidal adenomectomy. Neither of the two patients underwent external beam pituitary irradiation. The presence and extent of tumoral TSH hypersecretion was assessed by standard biochemical and dynamic endocrine testing, while tumor size was evaluated by conventional radiographic techniques. RESULTS: In both patients, TSH secretion was effectively suppressed by SMS-LAR. Moreover, administration of this compound halted further tumor growth, as well as resulted in improved patient comfort, for 12 and 10 months respectively. CONCLUSION: Our date corroborate earlier reports on the usefulness of SMS-LAR in the medical management of patients with TSPA's who have residual disease after initial pituitary surgery and/or irradiation.

Metastatic thyroid cancer unresponsive to conventional therapies: novel management approaches through translational clinical research.

In this contribution, we review the limitations of the currently applied "standard" treatments for well-differentiated, non-medullary thyroid cancer (ThyrCa), and describe the molecular and cellular biologic basis of potential novel therapeutic modalities currently under study and/or development. Conventional therapy for ThyrCa consists of total/near-total thyroidectomy, radioiodine (RAI or 131I), and long-term thyroid hormone "suppressive" therapy (THST). RAI therapy remains the cornerstone of the "standard" management strategies for metastatic ThyrCa, and when administered under optimal conditions can achieve either eradication or long-term clinical "control" of the disease. Despite increasing sophistication in the protocols using 131I over the last 30 years, no significant down-trend has been observed in the annual mortality rate for this disease, a fact reflecting the existence of a "core" population of patients with RAI-"resistant" disease. The molecular basis for this phenomenon is believed to be the progressive tumoral de-differentiation over time, with loss of (or marked decrease in) the expression of cellular components responsible for iodine uptake, organification and retention. Adjuvant methods to RAI, such as radiosensitizers and lithium carbonate, provide only marginal additional therapeutic effect. Further, the role of non-RAI-based modalities, such as secondary extensive metastatectomies with curative intent, external beam radiotherapy, and cytotoxic chemotherapy (mainly with doxorubicin-based regimens) has been unfortunately limited to highly selected cases. Palliative methods for acute clinical management of widely metastatic ThyrCa are also presented, along with anecdotal evidence for the potential therapeutic role for octreotide and its radiolabeled therapeutic peptide analogs, selective estrogen receptor modulators (SERM's), as well as bisphosphonates. Translational "bench-to-bedside" research has recently led to the identification of the transcriptional machinery as a valid target for future therapeutic efforts in ThyrCa. Indeed, pre-clinical studies with a variety or agents that affect the rate of thyroid-specific gene transcription, i.e. retinoids, DNA methyltransferase inhibitors, and histone deacetylase inhibitors, have shown their potential for induction of re-differentiation, growth inhibition, promotion of apoptosis and cell cycle regulation. These concerted genomic effects of the above compounds will probably yield novel types of therapies in the clinical arena, especially for RAI-non-avid tumors. Retinoid analogs have already been used in pilot studies in ThyrCa patients with limited success. These re-differentiating agents have raised our expectations for a type of therapy for this malignancy based on a solid molecular rationale, while future progress in the domains of tissue-targeted gene therapy and anti-angiogenesis is eagerly awaited.

Evidence for a common step in three different processes for modulating the kinetic properties of glucocorticoid receptor-induced gene transcription.

The dose-response curve of steroid hormones and the associated EC(50) value are critical parameters both in the development of new pharmacologically active compounds and in the endocrine therapy of various disease states. We have recently described three different variables that can reposition the dose-response curve of agonist-bound glucocorticoid receptors (GRs): a 21-base pair sequence of the rat tyrosine aminotransferase gene called a glucocorticoid modulatory element (GME), GR concentration, and coactivator concentration. At the same time, each of these three components was found to influence the partial agonist activity of antiglucocorticoids. In an effort to determine whether these three processes proceed via independent pathways or a common intermediate, we have examined several mechanistic details. The effects of increasing concentrations of both GR and the coactivator TIF2 are found to be saturable. Furthermore, saturating levels of either GR or TIF2 inhibit the ability of each protein, and the GME, to affect further changes in the dose-response curve or partial agonist activity of antisteroids. This competitive inhibition suggests that all three modulators proceed through a common step involving a titratable factor. Support for this hypothesis comes from the observation that a fragment of the coactivator TIF2 retaining intrinsic transactivation activity is a dominant negative inhibitor of each component (GME, GR, and coactivator). This inhibition was not due to nonspecific effects on the general transcription machinery as the VP16 transactivation domain was inactive. The viral protein E1A also prevented the action of each of the three components in a manner that was independent of E1A's ability to block the histone acetyltransferase activity of CBP. Collectively, these results suggest that three different inputs (GME, GR, and coactivator) for perturbing the dose-response curve, and partial agonist activity, of GR-steroid complexes act by converging at a single step that involves a limiting factor prior to transcription initiation.

Ectopic lingual thyroid: an otolaryngologic emergency beyond childhood.

Ectopic thyroid is rare and occasionally presents suddenly in childhood. Adult patients with thyroid ectopy who develop local symptoms commonly have an enlarged ectopic gland and hypothyroidism. We describe the first case of an adult patient who sudden presented with sudden dysphagia and dyspnea caused by a large lingual thyroid in clinical and biochemical euthyroidism. Treatment consisted of surgical removal of the ectopic gland and thyroid hormone replacement therapy.