text:
Abeloff's Clinical Oncology, 4th Edition
Part II – Problems Common to Cancer and its Therapy
Section G – Complications of Therapy
Chapter 65 – Endocrine Complications
Chapter 65 – Endocrine Complications
Manpreet K. Chadha,Donald L. Trump
Diagnostic Considerations
Evaluation and Treatment
Hypothalamic-Pituitary Axis
Syndrome of Inappropriate Antidiuretic Hormone Secretion
Endocrine dysfunction is an increasing cause of morbidity in cancer patients. Improved cancer therapies and new agents with endocrine side effects are primarily responsible for the increase. For example, the Childhood Cancer Survivor Study showed that one or more endocrine conditions were reported in 43% of childhood brain tumor survivors.[1] Timely recognition and management of endocrine dysfunction are essential to prevent further morbidity and impairment of quality of life in cancer patients. Table 65-1 outlines the causes of endocrine dysfunction in this population. Appropriate evaluation and treatment of common endocrinopathies are discussed in the latter sections of this chapter. A special section is included on surveillance of childhood cancer survivors for detection of late endocrinecomplications of various cancer therapies. Tumors of endocrine origin and neuroendocrine tumors are discussed in relevant sections of this textbook.
Table 65-1 -- Causes of Endocrine Dysfunction in Patients with Cancer
Historically, surgery has been used as a means of disrupting normal endocrine function with therapeutic intent.[2] Response rates of 15% to 30% were reported after hypophysectomy or adrenalectomy in advanced breast cancer. [3] [4] However, these procedures resulted in significant morbidity, including hypoadrenalism and hypopituitarism, requiring lifelong replacement therapy. For premenopausal women, ovarian ablation by surgical oophorectomy remains a therapeutic option in metastatic and adjuvant settings. These surgical procedures have been largely supplanted by pharmacologic agents such as luteinizing hormone-releasing hormone agonists along with aromatase inhibitors (inhibit adrenal steroidogenesis) to attain functional castration. [5] [6] Orchiectomy is considered a therapeutic option for men with metastatic prostate cancer.[7]
Normal pituitary function may be altered by surgical resection of a pituitary tumor or by injury to the pituitary stalk disrupting the hypothalamic-pituitary axis. In the former case, anterior pituitary hormones are primarily affected; in the latter case, both the anterior and posterior pituitary hormones are affected.
Similarly, resection of a tumor involving other endocrine glands may result in deficiencies of hormones secreted from these glands: thyroid (hypothyroidism), parathyroids (hypoparathyroidism), pancreas (diabetes mellitus), ovaries (hypogonadism), testes (hypogonadism), or adrenals (hypoadrenalism). Unilateral gland resection rarely results in noticeable hormone deficiencies. Extensive neck surgery and irradiation for advanced head and neck cancers may result in parathyroid hormone deficiency. This might be due to interference with the vascular supply of the parathyroids. Permanent hypoparathyroidism can result inadvertently from total thyroidectomy; the reported incidence is up to 40%.[8] Subtotal removal of parathyroid glands as a part of therapy for parathyroid hyperplasia can also cause hypoparathyroidism. It is often possible to preserve parathyroid function by careful surgical technique and/or by autotransplanting the parathyroid tissue to another part of body.
Endocrine organs may be intentionally or unavoidably exposed to ionizing radiation during treatment for malignancy, and high-dose radiation may result in endocrine dysfunction. Table 65-2 lists factors that are known to be associated with a high risk of endocrine dysfunction following radiation. Assessment of late effects of radiation may be difficult and subjective. Various groups have attempted to develop a scoring system to standardize toxicity reporting and description. An example is the LENT-SOMA (Late Effects on Normal Tissue–Subjective, Objective, Management and Analytic) to grade radiation-induced toxicity to the hypothalamic-pituitary axis and thyroid.[9] These scales grade the radiation-induced side effects on these organs exposed to irradiation in a manner similar to common toxicity criteria grading of adverse effects. Newer scales have been designed by the European Organization Treatment of Cancer and Radiation Therapy Oncology Group to grade toxicities related to radiation.[10] The late toxicity assessment of a treatment might depend on the toxicity scale used. The LENT-SOMA scale seems to be the most accurate scale so far. [11] [12]
Table 65-2 -- Risk Factors Associated with Increased Incidence of Radiation-Induced Endocrine Dysfunction
Radiation dose >30 Gy
Total body irradiation
Cranial irradiation
Age (children more sensitive)
Prior pituitary compromise by tumor/surgery
Length of follow-up
Hypothalamic-Pituitary Axis
Anterior pituitary dysfunction can result from irradiation of nasopharyngeal, extracranial, or primary brain tumors, especially those involving the pituitary. Total body irradiation as part of a bone marrow transplant preparative regimen[13] and prophylactic cranial radiation in patients with acute lymphoblastic leukemia can also cause hypopituitarism.[14] Approximately 19% of patients have a deficiency in one or more anterior pituitary hormones as early as 2 years after cranial irradiation for nasopharyngeal carcinoma.[15]
Data indicate that the hypothalamus is more radiosensitive and is damaged by lower doses of cranial radiation than is the pituitary.[16] Secondary pituitary atrophy evolves with time owing to impaired secretion of hypothalamic regulatory factors or direct radiation-induced damage. This necessitates prolonged follow-up and yearly testing of pituitary function in patients who have received cranial irradiation. The frequency, rapidity of onset, and severity of endocrine abnormalities correlate with the total radiation dose delivered to the hypothalamic-pituitary axis, the fraction size, younger age at irradiation, prior pituitary compromise by tumor and/or surgery, and the length of follow-up.[17]
Somatotrophes (cells that secrete growth hormone) are the most vulnerable to radiation damage; hence, growth hormone deficiency (GHD) is the most commonly seen endocrine dysfunction, following cranial irradiation. GHD may occur in isolation following irradiation of the hypothalamic-pituitary axis with doses less than 30 Gy. The clinical manifestations of GHD are most evident in the growing child: reduction in growth velocity and short stature. Some data suggest that children are more sensitive to radiation effects than are adults.[18] Although poor linear growth is very common in children with GHD, it is not universal or immediately apparent. Several studies suggest that the slowing of growth might not occur for the first year or two after onset of GHD. In postpubertal individuals, GHD is associated with a decrease in muscle mass along with an increase in adiposity.[19]
The hypothalamic neurons secrete gonadotropin-releasing hormone (GnRH) in pulses that are necessary for normal secretion of gonadotropins from the pituitary. This GnRH-pulse generation is affected differentially by the dose of radiation that is received. Abnormalities in gonadotrophin secretion are dose-dependent. Precocious puberty can occur after a radiation dose less than 30 Gy in girls and in both sexes equally with a radiation dose of 30 to 50 Gy. [20] [21] Radiation-induced precocious puberty might be caused by damage to inhibitory GABAergic neurons, leading to disinhibition and premature activation of GnRH neurons.[22] Higher-dose irradiation (>30 Gy) is associated with delayed sexual maturation due to gonadotropin deficiency from damage to GnRH secretory neurons.[23]
Deficiency in other pituitary hormones is less common. Five years after treatment, a study of 251 patients who had been treated for pituitary disease with external radiotherapy described an incidence of thyroid-stimulating hormone (TSH) deficiency of 9% at 20 Gy, increasing to 52% at 42 to 45 Gy.[24] A similar trend for incidence of adrenocorticotrophic hormone (ACTH) deficiency relation was seen. Hyperprolactinemia can be seen after high-dose radiotherapy (>40 Gy) and has been described in both sexes and all age groups but is most common in young women.[25] Constine and associates[26]described a 50% frequency of hyperprolactinemia in 32 patients who were treated with radiation for brain tumor with doses ranging from 39.6 to 70.2 Gy. Other investigators reported rates of 20% after treatment for nasopharyngeal carcinoma. Hyperprolactinemia can cause pubertal delay or arrest in children, galactorrhea and/or amenorrhea in women, and decreased libido and impotence in adult males.
Radiation-induced anterior pituitary hormone deficiencies are irreversible and progressive but are treatable with appropriate hormone replacement therapy. Careful surveillance and close follow-up with an endocrinologist are warranted.
Irradiation of the thyroid may produce hypothyroidism, Graves disease, silent thyroiditis, benign nodules, and thyroid cancers.[27] Hancock and colleagues described their experience with thyroid disease among patients treated with irradiation with or without chemotherapy for Hodgkin's disease at Stanford University.[28] Of 1787 patients, 1677 received irradiation to the thyroid. At 26 years of follow-up, the actuarial risk of thyroid disease was 67%. Hypothyroidism developed in the majority of the patients (47%). The risk of Graves disease was 7 to 20 times higher than that for normal subjects. The risk of thyroid cancer was noted to be 15.6 times the expected risk for normal subjects. The association between thyroid cancer and radiation is discussed in further detail in Chapter 75 . These data remind clinicians to follow thyroid function closely in patients who have been treated with upper mantle or cervical irradiation. Similar results were noted in the Childhood Cancer Survivor Study with an evaluable cohort of 1791 (959 males) Hodgkin's disease survivors. Among patients with Hodgkin's disease, the risk of hypothyroidism at 20 years from the time of diagnosis in those treated with 45 Gy or more was 50%.[29] Total dose of irradiation received has been shown to correlate with the incidence of hypothyroidism in many studies. [27] [28] [29] [30] There is controversy regarding the effect of age at the time of irradiation, gender, and association with the prior use of lymphangiograms. [27] [29]
Radiation-induced thyroid dysfunction is thought to be caused by damage to small thyroid vessels and to the glandular capsule. Focal and irregular follicular hyperplasia, hyalinization, and fibrosis beneath the vascular endothelium, lymphocytic infiltration, single and multiple adenomas, and thyroid carcinomas are histomorphologic features that are described in such patients. [27] [28]
A rare complication of external neck irradiation is acute radiation thyroiditis.[30] It is more commonly associated with therapeutic doses of radioiodine for thyroid diseases. Patients typically present with fever, pain in the anterior cervical region, and transient hyperthyroidism. Hyperthyroidism with a clinical picture that resembles Graves disease may be seen after neck irradiation for Hodgkin's disease.[31]The incidence is uncertain owing to the small number of cases reported. The clinical picture is characterized by diffuse thyroid enlargement, suppressed TSH, high levels of thyroid hormones, and development of thyroid autoantibodies. Ophthalmopathy, with or without overt hyperthyroidism, may be seen and is thought to be related to autoantibodies, similar to Graves disease.[32]
Parathyroid Glands
There are several studies that link prior head and neck irradiation and hyperparathyroidism. [33] [34] Cohen and colleagues[35] followed a cohort of patients who were treated with radiation to the tonsils before the age of 16 years. Among the 2923 patients, 32 patients were found to have clinical hyperparathyroidism. This is a 2.5-fold to 2.9-fold increase compared with the general population in the same age group. There is a long latency period (>25 years) between exposure and onset of hyperparathyroidism. Clinical presentations vary from asymptomatic increases in serum parathormone levels and hypercalcemia to disabling metabolic bone disease or nephrolithiasis. Individuals with a history of head and neck radiation should be monitored with calcium levels periodically (every 1 to 2 years) and indefinitely.[36]
Chemotherapy is not widely recognized to contribute to endocrine dysfunction; however, many data indicate to the contrary. Effects of systemic chemotherapy on ovarian and testicular function are discussed in Chapter 64 .
Hypothalamic-Pituitary Axis
In children, chemotherapeutic agents alone may disrupt growth hormone (GH) secretion even in the absence of cranial radiation. Roman and colleagues studied growth and GH secretion in 60 children who were in complete remission after treatment with chemotherapy and surgery for solid tumors.[37] They observed growth hormone deficiency in 45% of those studied and found that these children were more likely to have received high doses of chemotherapy (actinomycin D), but they could find no correlation with the duration of treatment, length of follow-up, tumor type, sex, or age. Depending on the intensity of chemotherapy, significant height loss can be detected in 40% to 70% of patients at 6-year follow-up.[38] Adjuvant chemotherapy can also aggravate growth failure in children with brain tumors receiving craniospinal radiation.[39]
Rose and colleagues reported hypothalamic dysfunction in patients with non–central nervous system tumors who received chemotherapy but did not receive cranial irradiation or traumatic brain injury.[40]Of 31 identified patients, GHD was identified in 15 (48%), central hypothyroidism in 16 (52%), and pubertal abnormalities in 10 (32%) patients. GHD and hypothyroidism were coexistent in eight patients (26%). Overall, 81% (n = 25) had GHD, hypothyroidism, precocious puberty, or gonadotropin deficiency.
The syndrome of inappropriate antidiuretic hormone (SIADH) secretion may result from the effects of many chemotherapeutic agents, either by potentiation of antidiuretic hormone (ADH) effect or by increased ADH secretion. The most commonly implicated agents are vinca alkaloids and cyclophosphamide. The vinca alkaloids are reported to stimulate the central release of ADH from the neurohypophyseal system,[41] whereas alkylating agents enhance renal tubular sensitivity to ADH.[42] Regardless of the mechanism, the result is an increase in water reabsorption by the distal tubules of the kidney, leading to volume expansion and dilutional hyponatremia. Many case reports also implicate platinum agents,[43] vinorelbine,[44] taxanes,[45] and methotrexate.[46] Clinically significant hyponatremia may occur with administration of these agents. Management requires fluid restriction and, at times, salt replacement.
Clinically evident thyroid dysfunction is rarely associated with the use of standard chemotherapy agents. However, a growing body of literature points to the increased prevalence of endocrine dysfunction after bone marrow transplantation, which may be seen following high doses of chemotherapy in absence of any radiation. There are reports of thyroid dysfunction in nearly 50% of allogeneic bone marrow transplant recipients treated with busulphan and cyclophosphamide alone.[47] Thyroid dysfunction may present as low T3 syndrome (free T4 normal, TSH normal, and free T3 below normal), chronic thyroiditis, and transient subclinical hyperthyroidism or hypothyroidism. Chemotherapy may potentiate radiation-induced damage to normal tissue. Among 32 patients treated for medulloblastoma in childhood, Paulino found that 18 patients developed hypothyroidism after a median time of 41 months after irradiation. Hypothyroidism was reported in 10 of the 12 patients (83%) who received 23.4 Gy plus chemotherapy (vincristine, N-[2-chloroethyl]-N′-cyclohexyl-N-nitrosourea [CCNU], cisplatin, or cyclophosphamide) and 6 of 10 (60%) of those who received 36 Gy plus chemotherapy (vincristine, CCNU, prednisone) versus only 2 of the 10 (20%) of those who received 36 GY radiation alone.[48]
Aminogluthemide, now an infrequently used drug to disrupt adrenal and peripheral steroid hormone synthesis, inhibits cholesterol conversion to pregnenolone. It causes thyroid dysfunction after long-term use due to blockade of iodination of tyrosine.[49] Figg and associates reported that 9 of 29 men who were treated with aminogluthemide for metastatic prostate cancer had clinical and biochemical evidence of hypothyroidism.[50]
Chemotherapeutic agents can also interfere with circulating thyroid hormones, thereby altering their free blood levels. 5-Fluorouracil increases total T3 and T4 levels, but free T4 index and TSH remain normal, indicating increased levels of thyroxine-binding globulin or enhanced binding capacity.[51] L-asparaginase causes transient thyroxine-binding globulin deficiency by diminishing hepatic synthesis and also inhibits TSH secretion from the pituitary, resulting in decreased total T4 as well as free T4 levels.[52] Transient hyperthyroidism after L-asparaginase therapy for acute lymphoblastic leukemia has also been observed.[53] These thyroid function abnormalities are mild and short-lived and generally do not require specific therapy.
In postmenopausal women, tamoxifen therapy is associated with changes in thyroid hormone concentrations, though patients may remain clinically euthyroid.[54] Mamby and colleagues undertook a randomized, placebo-controlled trial with tamoxifen 10 mg orally, twice daily, with 14 patients in each group.[55] Thyroid function test assessment before and 3 months after initiation of therapy was done. Serum thyroid-binding globulin increased, as did T4 uptake and T4 levels in the tamoxifen-treated group compared to placebo. TSH levels and free thyroxine index remained unchanged; patients were clinically euthyroid and did not require treatment.
A method of medically ablating or reducing adrenal function was sought for a number of years as an alternative to surgical resection of the adrenal glands. Surgical adrenalectomy was used primarily for the treatment of advanced breast cancer. Aminoglutethimide and ketoconazole both suppress adrenal function. These drugs appear to have their effect through their ability to inhibit important cytochrome P-450 isozymes, which are necessary for adrenal steroid synthesis. [56] [57] Aminoglutethimide, at doses of 1000 to 1500 mg/day, and ketoconazole, at doses of 800 to 1200 mg/day, produce adrenal insufficiency in 30% to 40% of patients. Although standard glucocorticoid treatment is generally required in these patients during treatment, mineralocorticoid replacement is usually not required. The antiadrenal effects of ketoconazole and aminoglutethimide are reversible with treatment discontinuation. Full recovery within 1 to 2 weeks is usual.
Mitotane (1-dichloro-2-[o-chlorophenyl]-2-[p-chlorophenyl]-ethane), is an oral chemotherapeutic agent that is used to treat adrenal carcinoma based on its potent antiadrenal effects.[58] It is used primarily to treat adrenal hyperfunction associated with adrenal carcinoma or ectopic production of corticotrophin. It has been reported to result in sustained remission for some patients with metastatic adrenal carcinoma with long-term administration.[59] Although the mechanism of action is incompletely understood, adrenal necrosis and permanent adrenal insufficiency can result, necessitating lifelong glucocorticoid administration.
Pancreatic exocrine or endocrine insufficiency attributable to chemotherapy is uncommon. Acute pancreatitis has been described as a complication of L-asparaginase therapy and can be fatal.[60] Although rare, several cases of diabetes mellitus have been associated with L-asparaginase therapy.[61] Hyperglycemia is usually transient and responds to intravenous fluids and drug discontinuation. A plausible mechanism may be inhibition of protein synthesis by L-asparaginase leading to interference with insulin production.[62] High triglyceride levels have been associated with L-asparaginase use, though it is not clearly associated with incidence of pancreatitis in these patients. Knoderer and colleagues retrospectively described 33 patients (13%) with asparaginase-associated pancreatitis in a cohort of 254 patients over a 5-year period.[63] Twelve cases were noted after Escherichia coli asparaginase, and 20 cases were noted after PEG-asparaginase therapy. The incidence of pancreatitis was found to be independent of the individual or cumulative asparaginase dose. The interval to pancreatitis diagnosis was longer for PEG-asparaginase than for E. coli asparaginase (P = 0.02). Patients who received prednisone (P = 0.02) and daunomycin (P = 0.006) were more likely to develop pancreatitis than were those who received dexamethasone (P = 0.04). Use of other chemotherapy agents was not observed to have a significant effect on the incidence of pancreatitis.
High-dose cytarabine can rarely result in pancreatitis. Siemers and colleagues described two patients with evidence of pancreatitis among 30 patients treated with cytarabine.[64] Prior therapy with L-asparaginase was found in another small series of patients who received cytarabine and developed pancreatitis.[65]
Streptozotocin is a nitrosurea that is used primarily for the treatment of pancreatic endocrine tumors. In preclinical models, streptozotocin causes beta cell necrosis and insulin-dependent diabetes in many species.[66] Mild glucose intolerance has been described in patients receiving this agent; however, specific treatment is rarely required.[67]
Androgen ablation therapy may also be associated with diabetes. Keating and colleagues showed an increased incidence of diabetes in prostate cancer patients receiving GnRH agonist. A potential mechanism is the increase in body fat mass associated with hypogonadism, which results in insulin resistance.[68]
Biologic agents are increasingly important in cancer treatment, and various endocrine complications are being recognized with the use of these agents.
Immune therapies may cause thyroid dysfunction. Atkins and colleagues[69] were the first to describe an association between therapy with recombinant interleukin-2 and thyroid abnormalities. Interleukin-2 therapy is known to be associated with both hypothyroidism and hyperthyroidism, though the former is more common.[70] In Atkins and colleagues' original report, seven patients (21%) had laboratory evidence of hypothyroidism, a decline in the serum thyroxine concentration and serum free thyroxine index, and an increase in the serum TSH concentration 6 to 11 weeks after treatment.[69] All five symptomatic patients had borderline or elevated serum antimicrosomal antibody titers after treatment; two had serum antibodies to thyroglobulin. Five of the seven patients with hypothyroidism (71%) but only 5 of the 27 euthyroid patients (19%) had evidence of tumor regression (P < 0.02). Fifteen patients (47%) became hypothyroid with high serum TSH levels within 60 to 120 days after the start of treatment. The proposed mechanism is autoimmune with development of antithyroid antibodies. Proposed mechanisms are that either the interleukin-2 treatment itself triggers autoreactive B-cell clones or cellular and/or cytokine-mediated thyroid destruction leads to activation of autoreactive B-cell clones.
Hypothyroidism is a recognized complication of tyrosine kinase inhibitors. Sunitinib maleate is an oral tyrosine kinase inhibitor that was recently approved for the treatment of gastrointestinal stromal tumors and renal cell carcinoma. Desai and colleagues reported hypothyroidism in patients undergoing sunitinib therapy.[71] One potential mechanism may be sunitinib-induced destructive thyroiditis through follicular cell apoptosis. Sunitinib is also a RET/PTC tyrosine kinase inhibitor that is involved in pathogenesis of papillary thyroid cancer and perhaps affects normal thyroid function as well.
Imatinib also interacts with thyroid hormone replacement and results in increased TSH levels in hypothyroid individuals who are on levothyroxine therapy. However, it does not appear to have a direct effect on the thyroid but alters the levels of thyroxine binding protein.[72] Berman and colleagues reported hypophosphatemia and associated changes in bone mineral metabolism in patients taking imatinib for either chronic myelogenous leukemia or gastrointestinal stromal tumors.[73] Patients were found to have high levels of urinary phosphate and markedly decreased serum levels of osteocalcin and N-telopeptide, indicative of reduced bone turnover. Imatinib inhibits platelet-derived growth factor receptor, which in a rat model has been demonstrated to have a critical role in skeleton development.
Interferon-beta (IFN-β) and interferon-alpha (IFN-α) may both increase ACTH, prolactin, growth hormone, and cortisol levels in patients.[74] An assessment of IFN-α-induced endocrine stimulation in patients with myeloproliferative disorders revealed that on day 1 of therapy, a significant stimulation of the hypothalamic-pituitary axis was apparent, an effect that disappeared by the third week of therapy.[75] The acute stimulatory effect of IFN-α on cortisol release appears to be mediated by the release of hypothalamic corticotropin-releasing hormone. There are reports of alterations in the levels of sex hormones during IFN therapy, and male sexual dysfunction has been noted.[76]
Clinicians should keep in mind that there are limited data regarding the effects of many new agents and one must be alert to endocrine dysfunction in patients receiving such drugs.
A detailed history, including treatment history and physical examination, should be done in any patient who is suspected of having endocrine dysfunction. Evaluation should be directed by this information and the location and type of tumor. The initial approach to the diagnostic workup is outlined in the following sections. Endocrinology consultation should be sought for more complex and multisystem involvement. Table 65-3 shows a brief outline of evaluation of common endocrine disorders. The workup for gonadotropin deficiency and hormone replacement is discussed in detail in Chapter 64 .
Table 65-3 -- Diagnostic Evaluation of Common Endocrine Disorders
Confirmatory Tests
GH deficiency
Fatigue, poor stamina, hypoglycemia
Slow growth velocity, delayed puberty, truncal fat distribution
IGF-1, IGFBP-3, and bone maturation
Insulin hypoglycemia test, arginine, L-dopa, clonidine
Hypothyroidism (primary or secondary)
Fatigue, cold intolerance, weight gain, cognitive dysfunction, mental retardation, constipation, growth failure, dry skin, depression, menstrual disturbances
Slow movement and slow speech, delayed relaxation of tendon reflexes, bradycardia, coarse skin, periorbital edema, macroglossia
Free T4, TSH, and bone maturation
TSH surge
Hyperactivity, tremors, diarrhea, sweating, weight loss, heat intolerance
Atrial fibrillation, lid lag, proptosis, goiter
Free T4, T3, and TSH
Radioiodine uptake scan
Adrenal insufficiency (primary or secondary)
Dehydration, hyperpigmentation, weakness, fatigue
Electrolyte disturbance, hypotension, nausea, vomiting
Early morning serum cortisol level
Low- or high-dose ACTH stimulation test
Hypothalamic-Pituitary Axis Disorders
Growth Hormone Deficiency
The assessment of pituitary GH production is difficult because GH secretion is pulsatile and serum GH levels are often low between the pulses. Therefore, measurement of a single serum GH level is of limited use in diagnosing GHD. Serum insulin-like growth factor (IGF-1) and IGF binding protein-3 (IGFBP-3) concentrations may be measured as a surrogate marker for GH production, and further evaluation is indicated if these results are below the mean for normal children of the same age. An IGF-1 level below 84 ng/mL using the Esoterix assay reportedly is highly indicative of GHD.[77]Confirmation can be done by GH secretion provocative tests.
According to the consensus guidelines for the diagnosis and treatment of adults with GH deficiency, the insulin hypoglycemia test is the gold-standard GH provocative test.[78] According to the Food and Drug Administration, GHD is diagnosed if the maximum stimulated serum GH concentration is less than 5.1 μg/L (polyclonal radioimmunoassay) or less than 2.5 μg/mL (immunochemiluminescent assay).[79] Even though reliable, this test requires strict monitoring. The insulin hypoglycemia test is contraindicated in debilitated patients, those with cardiovascular or cerebrovascular disease, and those with a history of seizure, abnormal electroencephalogram (EEG), or history of brain surgery. [77] [78] [79] In these patients, the combined arginine/GHRH stimulation test may be used. The arginine stimulation test involves intravenous infusion of 0.5 g/kg body weight (to a maximum of 30 g) of arginine given over 30 minutes and measuring serum growth hormone level at 0, 30, 60, 90, and 120 minutes. Though historically the insulin hypoglycemia test was considered the gold standard for GHD, the arginine-GHRH test is much safer, is 95% sensitive and 91% specific (at a cutoff of 4.1 μg/L), and has essentially replaced the former.[80]
The diagnosis of GHD in childhood is a complex process that requires clinical and growth assessment combined with biochemical tests and radiologic evaluation. GHD may be an isolated finding or a component of multiple pituitary hormone deficiency. In a child with clinical criteria for GHD, a peak GH concentration less than 10 μg/L has traditionally been used to support the diagnosis after a provocative GH test.[81] Supportive evidence is indicated by very short height (more than 2.5 standard deviations below the mean height for normal children of the same age), delayed bone age, poor growth velocity (less than twenty-fifth percentile), and a predicted adult height substantially below the mean parental height.[77] IGF-I/IGFBP-3 levels and GH provocation tests should be done after hypothyroidism has been excluded as a cause of slow growth. Great care should be taken in using insulin or glucagon provocative tests in a young child, and testing should be monitored by an experienced team.
Children with proven GHD should receive GH therapy as soon as possible after diagnosis. The goal of therapy is to maximize height attained before puberty. The usual starting dose of GH is 25 to 50 μg/kg/day, administered subcutaneously in the evening. [72] [73] Each dose produces a pharmacologic level of GH for approximately 12 hours. Evaluation of the growth response and adjustment of GH dose should occur every 4 to 6 months, and assessment should include measurement of height, weight, and arm span. GH dose is increased as weight gain occurs to maintain a stable dose per kilogram of body weight. Serum IGF-1 measurements are recommended yearly. If IGF-1 increases above the upper limits of normal for age and gender, the GH dose should be decreased.
GH therapy in adults is approved by the Food and Drug Administration only if there is evidence of hypothalamic or pituitary disease and a subnormal serum GH response to a provocative test. The goal of the therapy is to improve muscle and cardiac function, restore normal body composition, and improve serum lipids. The usual starting dose for adults between 30 to 60 years of age is 300 μg/day; the dose is increased every 1 to 2 months by 100 to 200 μg/day, guided by clinical response and measurement of serum GH levels. [77] [78]
The presenting symptoms of hyperprolactinemia include amenorrhea, galactorrhea, impotence, and infertility. The diagnosis of hyperprolactinemia is made by a random serum prolactin level measurement. Dynamic testing of the lactotrophin reserve with thyrotropin-releasing hormone is not useful because it does not differentiate between the different causes of hyperprolactinemia.[82] Hypothyroidism must also be ruled out as a cause of clinical findings, and careful review of medications should be done to rule out drug-induced hyperprolactinemia.
Dopamine released from hypothalamic nerve endings acts as a prolactin inhibitory factor, and dopaminergic agonists are useful in the treatment of hyperprolactinemia. Commonly used agents include bromocriptine and cabergoline. The most common side effects of these drugs are nausea, postural hypotension, and mental fogginess. Less common side effects include nasal stuffiness, depression, Raynaud phenomenon, alcohol intolerance, and constipation. The usual starting dose is 0.25 mg of cabergoline twice a week or 1.25 mg of bromocriptine once a day. The doses can be increased on the basis of serum prolactin level and the side effect profile.
Thyroid Disorders
Primary hypothyroidism is characterized by a high serum TSH (normal range: 0.5 to 5 mU/L) concentration and a low serum free T4 concentration (normal range- 0.8 to 1.8 ng/dL). Secondary hypothyroidism is characterized by a low serum T4 concentration and a serum TSH concentration that is not appropriately elevated.[83] To distinguish between pituitary and hypothalamic causes of hypothyroidism, thyrotropin-releasing hormone stimulation test and/or imaging studies of the sellar and suprasellar region should be done. Patients who are diagnosed with central hypothyroidism should also be evaluated for coexistent adrenocortical, gonadal, posterior pituitary, and, in children, growth hormone function. As was noted previously, patients with cranial irradiation or traumatic brain injury are at high risk for panhypopituitarism.
Primary hyperthyroidism is associated with low TSH and high free T4. Graves disease is associated with uniformly high 24-hour radioiodine uptake, while toxic adenoma is associated with focal high uptake. If free T4 and T3 are high with a normal or high TSH in a clinically hyperthyroid patient, pituitary magnetic resonance imaging should be done to look for a pituitary mass (TSH-secreting adenoma).
Thyroid hormone replacement with levothyroxine (T4) is usually sufficient. The goal of therapy is to attain normal TSH (in primary hypothyroidism) and free T4 levels (in secondary hypothyroidism). The average replacement dose of T4 in adults is approximately 1.6 μg/kg body weight per day. Treatment with liothyronine (T3) may be required in patients with no response to levothyroxine therapy or in patients with myxedema coma.
Thyroid ablation with surgery, radioiodine, or pharmacologic agents (propylthiouracil, methimazole) should be considered in patients with hyperthyroidism. Beta blocker therapy is used as a clinical adjunct in most patients. The goal of therapy is to keep the TSH and T3 and T4 in the normal range. Surgery is indicated primarily in patients who have large or obstructive goiter.
Syndrome of Inappropriate Antidiuretic Hormone
SIADH is characterized by hyponatremia, a low plasma osmolality, an inappropriately elevated urine osmolality (above 100 mosmol/kg), and a high urinary sodium concentration (usually above 40 mEq/L). Other supportive findings include low BUN and serum uric acid concentration, normal plasma creatinine concentration, normal acid-base and potassium balance, and normal adrenal and thyroid function.[84]
Water restriction is the mainstay of therapy in asymptomatic hyponatremia and in chronic SIADH. Severe, symptomatic, or resistant hyponatremia requires the administration of salt tablets or hypertonic saline administration. A loop diuretic (such as furosemide once or twice a day) may be used to enhance the effect of fluid reduction, since it directly interferes with the countercurrent concentrating mechanism by decreasing sodium and chloride reabsorption in the medullary portion of the loop of Henle.[85] In patients who remain refractory, demeclocycline (300 to 600 mg twice a day) or lithium may be used.[86] These drugs act on the collecting tubule cell to diminish its responsiveness to ADH, thereby increasing water excretion. ADH receptor antagonists are being evaluated that are selective for the V2 (antidiuretic) receptor and may thus reverse the hyponatremia. Conivaptan blocks V2 and V1a receptors and is available in parenteral form.[87]
Primary hyperparathyroidism is characterized by elevated parathormone level and hypercalcemia. Supportive findings include low serum phosphate level, an increase in 24-hour urinary calcium excretion, a decrease in serum calcitriol and 25(OH) cholecalciferol, and an increase in biochemical markers of bone turnover (collagen cross-links, osteocalcin, bone-specific alkaline phosphatase). Patients may present with classic symptoms of the disease (nephrolithiasis or bone disease), or they may have nonspecific symptoms such as fatigue, weakness, mild depression, vague abdominal pain, and constipation.
Patients should be advised to avoid factors that can aggravate hypercalcemia, including thiazide diuretic and lithium carbonate therapy, volume depletion, prolonged bed rest or inactivity, and a high-calcium diet (>1000 mg/day). Daily vitamin D intake of 400 to 600 IU daily should be maintained, as vitamin D deficiency stimulates parathormone secretion and bone resorption and therefore is deleterious in patients with primary hyperparathyroidism. Surgical removal of the parathyroid glands remains the mainstay of therapy in most patients. Medical therapy involves estrogen plus progestin, bisphosphonates, or raloxifene. These drugs inhibit bone resorption and increase bone density and possibly lower serum calcium concentrations in patients with hyperparathyroidism. Calcimimetics and vitamin D analogs act by suppressing parathyroid hormone release and counteract the effects of hyperparathyroidism at the level of the parathormone receptor. Calcimimetics are currently being studied for primary and secondary hyperparathyroidism.[88]
Adrenal Disorders
There is controversy about the optimal biochemical approach to diagnosis of corticotropin deficiency. In moderate to severe corticotropin deficiency, the early morning serum cortisol levels are consistently less than 250 nM. A corticotropin stimulation test may be used to confirm the diagnosis. Both low-dose (1 μg) and high-dose (250 μg) corticotropin stimulation tests are useful to distinguish primary from pituitary (secondary) causes of adrenal insufficiency. Serum cortisol levels are measured at 0, 30, and 60 minutes after intravenous administration of corticotropin. If corticotropin and adrenal secretion are normal, the serum cortisol levels should increase to 20 μg/dL or higher. In patients with severe corticotropin deficiency, the serum cortisol response will be lower or absent as a result of adrenal atrophy. Primary adrenal insufficiency is characterized by low response to both low-dose and high-dose corticotropin stimulation tests. Acute adrenal crisis is an oncologic emergency. Electrolyte disturbances such as hyponatremia, hyperkalemia, azotemia, hypercalcemia, and hypoglycemia are common.
Adrenal insufficiency requires glucocorticoid supplementation and at times mineralocorticoid supplementation. Pituitary or isolated ACTH deficiency is not characterized by mineralocorticoid deficiency. Patients with symptomatic adrenal insufficiency should be treated with hydrocortisone or cortisone in the early morning and afternoon. The usual initial oral dose is 25 mg of hydrocortisone (15 mg in the morning and 10 mg in the afternoon). This may be decreased over time, with the goal of using the minimal effective dose to prevent weight gain and osteoporosis.[89] Patients with primary adrenal insufficiency require mineralocorticoid replacement with fludrocortisone (0.05 to 2 mg orally each day). During periods of stress, patients with adrenal insufficiency require higher-than-usual doses of hydrocortisone, and in severe illness, they might require intravenous high-dose hydrocortisone therapy due to acute adrenal crisis. Box 65-1 outlines a treatment algorithm for acute adrenal crisis, which should be treated as an oncologic emergency.
Box 65-1
With improved therapy for most childhood cancers, there is an increasing population of childhood cancer survivors.[90] Such individuals are at risk for long-term endocrine complications related to the tumor and/or the treatment received. The risk of a particular endocrinopathy depends on the tumor location and the dose and duration of radiotherapy and chemotherapy received. Box 65-2 depicts a summary of recommended yearly surveillance in childhood cancer survivors for endocrine complications.[91] Close follow-up should be performed every 4 to 6 months if the initial tests are normal but the child remains symptomatic.
Box 65-2
Children typically exhibit catch-up growth and weight gain after completion of therapy. Some children transiently develop breast buds corresponding to this period of newly improved nutrition. These children should be examined every 3 to 6 months to evaluate for precocious puberty. Assessment of Tanner stage of pubertal development is useful to assess for precocious or delayed puberty. Further testing should be guided by the physical findings.
Surveillance for adrenocortical deficiency is indicated primarily for high-risk patients such as those who received cranial irradiation in excess of 40 Gy. There is controversy regarding how long the surveillance should be carried out. The surveillance is guided largely by the pattern of growth and development. If normal growth and pubertal development are attained, the surveillance can be stopped.
Endocrine disorders are common in patients with cancer and are related primarily to cancer therapy. Careful clinical examination and yearly surveillance should be done in cancer survivors. A high degree of clinical suspicion is necessary in patients who are on newer therapies with which there is limited experience. Most endocrine disorders are readily treatable, and an accurate diagnosis should be pursued aggressively.
- Gurney JG, Kadan-Lottick NS, Packer RJ, et al: Endocrine and cardiovascular late effects among adult survivors of childhood brain tumors: Childhood Cancer Survivor Study. Cancer2003; 97:663-673.
- Beatson GT: On the treatment of inoperable cases of carcinoma of the mamma: suggestions for new methods of treatment. Lancet1896; 2:104-107.162–165
- Schwarz M, Tindall GT, Nixon DW: Transsphenoidal hypophysectomy in disseminated breast cancer. South Med J1981; 74:315-317.
- Silverstein MJ, Byron RL, Yonemoto RH: Bilateral adrenalectomy for advanced breast cancer. Surgery1975; 77:825-832.
- Buzdar A: Endocrine therapy in the treatment of metastatic breast cancer. Semin Oncol2001; 28:291-304.
- Dees EC, Davidson NE: Ovarian ablation as adjuvant therapy for breast cancer. Semin Oncol2001; 28:322-331.
- Samson DJ, Seidenfeld J, Schmitt B, et al: System-atic review and meta-analysis of monotherapy compared with androgen blockage for patients with advanced prostate carcinoma. Cancer2002; 95:361-376.
- Lo CY: Parathyroid autotransplantation during thryoidectomy. Aust N Z J Surg2002; 72:902-907.
- LENT SOMA tables. Radiother Oncol1995; 3:17-60.
- Hoeller U, Tribius S, Kuhlmey A, et al: Increasing the rate of late toxicity by changing the score? A comparison of RTOG/EORTC and LENT/SOMA scores. Int J Radiat Oncol Biol Phys2003; 55:1013-1018.
- Dennis F, Garaud P, Bardet E, et al: Late toxicity results of the GORTEC 94-01 randomized trial comparing radiotherapy with concomitant radiochemotherapy for advanced-stage oropharynx carcinoma: comparison of LENT/SOMA, RTOG/EORTC, and NCI-CTC scoring systems. Int J Radiat Oncol Biol Phys2003; 55:93-98.
- Anacak Y, Yalman D, Ozsaran Z, Haydaroglu A: Late radiation effects to the rectum and bladder in gynecologic cancer patients: the comparison of LENT/SOMA and RTOG/EORTC late-effects scoring systems. Int J Radiat Oncol Biol Phys2001; 50:1107-1112.
- Mills W, Chatterjee R, McGarrigle HH, et al: Partial hypopituitarism following total body irradiation in adult patients with hematological malignancy. Bone Marrow Transplant1994; 14:471-473.
- Hata M, Ogino I, Aida N, et al: Prophylactic cranial irradiation of acute lymphoblastic leukemia in childhood: outcomes of late effects on pituitary function and growth in long term survivors. Int J Cancer2001; 96:117-124.
- Lam KS, Tse VK, Wang C, et al: Early effects of cranial irradiation on hypothalamic-pituitary function. J Clin Endocrinol Metab1987; 64:418-424.
- Spoudeas HA, Hindmarsh PC, Matthews DR, Brook CG: Evolution of growth hormone neurosecretory disturbance after cranial irradiation for childhood brain tumours: a prospective study. Journal of Endocrinology1996; 150:329-342.
- Darzy KH, Shalet SM: Hypopituitarism as a consequence of brain tumours and radiotherapy. Pituitary2005; 8:203-211.
- Brennan B, Shalet S: Endocrine late effects after bone marrow transplant. Br J Haematol2002; 118:58-66.
- Salamon F, Cuneo R, Hesp R, et al: The effects of treatment with recombinant human growth hormone on body composition and metabolism in adults with growth hormone deficiency. N Engl J Med1989; 321:1797-1803.
- Didcock E, Davies HA, Didi M, et al: Pubertal growth in young adults survivors of childhood leukemia. J Clin Oncol1995; 13:2503-2507.
- Darzy KH, Shalet SM: Hypopituitarism as a consequence of brain tumours and radiotherapy. Pituitary2005; 8:203-211.
- Roth C, Schmidberger H, Schaper O, et al: Cranial irradiation of female rats causes dose-dependent and age-dependent activation or inhibition of pubertal development. Pediatr Res2000; 47:586-591.
- Muller J: Disturbance of pubertal development after cancer treatment. Best Pract Res Clin Endocrinol Metab2002; 16:91-103.
- Littley MD, Shalet S, Morgasnstern G, et al: Radiation-induced hypopituitarism is dose-dependent. Clin Endocrinol (Oxf)1989; 31:363-373.
- Sklar CA, Constine LS: Chronic neuroendocrinological sequelae of radiation therapy. Int J Radiat Oncol Biol Phys1995; 31:1113.
- Constine LS, Woolf PD, Cann D, et al: Hypothalamic-pituitary dysfunction after radiation for brain tumors. N Engl J Med1993; 328:87-94.
- Hancock SL, McDougall IR: Thyroid abnormalities after therapeutic external radiation. Int J Radiat Oncol Biol Phys1995; 31:1165-1170.
- Hancock SL, Cox RS, McDougall IR: Thyroid diseases after treatment of Hodgkin's disease. N Engl J Med1991; 325:599-605.
- Sklar C, Whitton J, Mertens A, et al: Abnormalities of the thyroid in survivors of Hodgkin's disease: data from the Childhood Cancer Survivor Study. J Clin Endocrinol Metab2000; 85:3227-3232.
- Jereczek-Fossa BA, Alterio D, Jassem J, et al: Radiotherapy-induced thyroid disorders. Cancer Treat Rev2004; 30:369-384.
- Loeffler JS, Tarbell NJ, Garber JR, et al: The development of Graves' disease following radiotherapy for Hodgkin's disease. Int J Radiat Oncol Biol Phys1988; 14:175-178.
- Jacobson DR, Fleming BJ: Graves' disease with ophthalmopathy following radiotherapy for Hodgkin disease. Am J Med Sci1984; 288:217-220.
- Christmas TJ, Chapple CR, Noble JG, et al: Hyperparathyroidism after neck irradiation. Br J Surg1988; 75:873-874.
- Ron E, Saftlas AF: Head and neck radiation carcinogensis: epidemiologic evidence. Otolaryngol Head Neck Surg1996; 115:403-408.
- Cohen J, Gierlowski TC, Schneider AB: A prospective study of hyperparathyroidism in individuals exposed to radiation in childhood. JAMA1990; 264:581-584.
- Schneider AB, Gierlowski TC, Shore-Freedman E, et al: Dose-response relationships for radiation-induced hyperparathyroidism. J Clin Endocrinol Metab1995; 80:254-257.
- Roman J, Vilaaizan CJ, Garcia-Foncillas J, et al: Growth and growth hormone secretion in children with cancer treated with chemotherapy. J Pediatr1997; 131:105-112.
- Spoudeas H: Growth and endocrine function after chemotherapy and radiotherapy in childhood. Eur J Cancer2002; 38:1748-1759.
- Olshan JS, Gubernick J, Packer J, et al: The effects of adjuvant chemotherapy on growth in children with medulloblastoma. Cancer1992; 70:2013-2017.
- Rose SR, Schreiber RE, Kearney NS, et al: Hypothalamic dysfunction after chemotherapy. J Pediatr Endocrinol Metab2004; 17:55-66.
- Antony A, Robinson WA, Roy C, et al: Inappropriate antidiuretic hormone secretion after high dose vinblastine. J Urol1980; 123:783-784.
- Campbell DM, Atkinson A, Gillis D, et al: Cyclophosphamide and water retention: mechanism revisited. J Pediatr Endocrinol Metab2000; 13:673-675.
- Ishii K, Aoki Y, Sasaki M, et al: Syndrome of inappropriate secretion of antidiuretic hormone induced by intraarterial cisplatin chemotherapy. Gynecol Oncol2002; 87:150-151.
- Garrett CA, Simpson Jr TA: Syndrome of inappropriate secretion of antidiuretic hormone associated with vinorelbine therapy. Ann Pharmacother1998; 32:1306-1309.
- Langer-Nitsche C, Luck HJ, Heilmann M: Severe syndrome of inappropriate antidiuretic hormone secretion with docetaxel treatment in metastatic breast cancer. Acta Oncol2000; 39:1001.
- Frahm H, von Hulst M: Increased secretion of vasopressin and edema formation in high dosage methotrexate therapy. Z Gesamante Int Med1988; 43:411-414.
- Tauchmanova L, Selleri C, Rosa GD: High prevalence of endocrine dysfunction in long-term survivors after allogeneic bone marrow transplantation for hematologic diseases. Cancer2002; 95:1076-1084.
- Paulino AC: Hypothyroidism in children with medulloblastoma: a comparison of 3600 and 2340 cGy craniospinal radiotherapy. Int J Radiat Oncol Biol Phys2002; 53:543-547.
- Cytadren (aminoglutethimide). Product information, East Hanover, NJ, Novartis Pharmaceuticals Corporation, 2000.
- Figg WD, Thibault A, Sartor AO, et al: Hypothyroidism associated with aminoglutethimide in patients with prostate cancer. Arch Intern Med1994; 154:1023-1025.
- Shalet SM: Endocrine sequelae of cancer therapy. Eur J Endocrinol1996; 135:135-143.
- Garnick MB, Larsen PR: Acute deficiency of thyroxine binding globulin during L-asparaginase therapy. N Engl J Med1979; 301:252-253.
- Heidemann PH, Stubbe P, Beck W: Transient secondary hypothyroidism and thyroxine binding globulin deficiency in leukemic children during polychemotherapy: An effect of L-asparaginase. Eur J Pediatr1981; 136:291-295.
- Kostoglou-Athanassiou I, Ntalles K, Markopoulous G, et al: Thyroid function in postmenopausal women with breast cancer on tamoxifen. Eur J Gynaecol Oncol1998; 19:150-154.
- Mamby CC, Love RR, Lee KE: Thyroid function test changes with adjuvant tamoxifen therapy in postmenopausal women with breast cancer. J Clin Oncol1995; 13:854-857.
- Santen RJ, Samojlik E, Lipton A: Kinetic, hormonal and clinical studies with aminoglutethimide in breast cancer. Cancer1977; 39:2948-2958.
- Trump DL, Havlin KH, Messing EM: High dose ketoconazole in advanced hormone-refractory prostate cancer: endocrinologic and clinical effects. J Clin Oncol1989; 7:1093-1098.
- Lubitz JA, Freeman L, Ikun R: Mitotane in inoperable adrenal cortical carcinoma. JAMA1973; 223:1109-1112.
- Ilias I, Alevizaki M, Philippou G, et al: Sustained remission of metastatic adrenal carcinoma during long-term administration of low-dose mitotane. J Endocrinol Invest2001; 24:532-535.
- Lamelas RG, Chapchap P, Magalhaes AC, et al: Successful management of a child with asparaginase-induced hemorrhagic pancreatitis. Med Pediatr Oncol1999; 32:316.
- Jaffe N: Diabetes mellitus secondary to L-asparaginase therapy. J Pediatr1972; 81:1270.
- Ettinger LJ, Ettinger AG, Aiavaramis VI, et al: Acute lymphoblastic leukemia: a guide to asparaginase and pegasparase therapy. BioDrugs1997; 7:30-39.
- Knoderer HM, Robarge J, Flockhart JA: Predicting asparaginase-associated pancreatitis. Pediatr Blood Cancer2007; 49:634-639.
- Siemers RF, Freidenberg RF, Norfleet RG: High-dose cytosine arabinoside-associated pancreatitis. Cancer1985; 56:1940-1942.
- Altman AJ, Dindorf P, Quinn JJ: Acute pancreatitis in association with cytosine arabinoside therapy. Cancer1982; 49:1384-1386.
- Yang H, Wright J: Human (beta) cells are exceedingly resistant to streptozocin in vivo. Endocrinology2002; 143:2491-2495.
- Broder LE, Carter SK: Pancreatic islet cell carcinoma: results of treatment with streptozocin in 52 patients. Ann Intern Med1973; 79:108-118.
- Keating NL, O'Malley AJ, Smith MR, et al: Diabetes and cardiovascular disease during androgen deprivation therapy for prostate cancer. J Clin Oncol2006; 24:4448-4456.
- Atkins MB, Mier JW, Parkinson DR: Hypothyroidism after treatment with interleukin-2 and lymphokine activated killer cells. N Engl J Med1988; 318:1557-1563.
- Weijl NI, Van der Harst D, Brand A, et al: Hypothyroidism during immunotherapy with interleukin-2 is associated with antithyroid antibodies and response to treatment. J Clin Oncol1993; 11:1376-1383.
- Desai J, Yassa L, Margusse E, et al: Hypothyroidism after sunitinib treatment for patients with gastrointestinal stromal tumors. Ann Intern Med2006; 145:660.
- De Groot JW, Zonnenberg BA, Plukker JT, et al: Imatinib induces hypothyroidism in patients receiving levothyroxine. Clin Pharmacol Ther2005; 78:433-438.
- Berman E, Nicolaides M, Maki RG, et al: Altered bone and mineral metabolism in patients receiving imatinib mesylate. N Engl J Med2006; 354:2006-2013.
- Nolten WE, Goldstein D, Lindstrom M, et al: Effects of cytokines on the pituitary-adrenal axis in cancer patients. J Interferon Res1993; 13:349-357.
- Gisslinger H, Svoboda T, Clodi M, et al: Interferon-alpha stimulates the hypothalamic-pituitary-adrenal axis in vivo and in vitro. Neuroendocrinology1993; 57:489-495.
- Jones TH, Wadler S, Hupart KH: Endocrine-mediated mechanisms of fatigue during treatment with interferon-alpha. Semin Oncol1998; 25(suppl 1):54-63.
- Hartman ML, Crowe BJ, Biller BM, et al: Which patients do not require a GH stimulation test for the diagnosis of adult GH deficiency?. J Clin Endocrinol Metab2002; 87:477-485.
- Molitch ME, Clemmons DR, Malozowski S, et al: Evaluation and treatment of adult growth hormone deficiency: an Endocrine Society Clinical Practice Guideline. J Clin Endocrinol Metab2006; 91:1621-1634.
- Vance ML, Mauras N: Growth hormone therapy in adults and children. N Engl J Med1999; 341:1206.
- Biller BM, Samuels MH, Zagar A, et al: Sensitivity and specificity of six tests for the diagnosis of adult growth hormone deficiency. J Clin Endocrinol Metab2002; 87:2067-2079.
- GH Research Society : Consensus guidelines for the diagnosis and treatment of growth hormone deficiency in childhood and adolescence: summary statement of the GH research society. J Clin Endocrinol Metab2000; 85:3990-3993.
- Suliman AM, al-Saber F, Hayes F: Hyperprolactinemia: analysis of presentation, diagnosis and treatment in the endocrine service of a general hospital. Ir Med J2000; 93:74-76.
- Dayan CM: Interpretation of thyroid function tests. Lancet2001; 357:619-624.
- Clayton JA, Le Jeune IR, Hall IP: Severe hyponatraemia in medical in-patients: aetiology, assessment and outcome. QJM2006; 99:505-511.
- Decaux G, Waterlot Y, Genette F, Mockel J: Treatment of the syndrome of inappropriate secretion of antidiuretic hormone with furosemide. N Engl J Med1981; 304:329-330.
- Forrest Jr JN, Cox M, Hong C, et al: Superiority of demeclocycline over lithium in the treatment of chronic syndrome of inappropriate secretion of antidiuretic hormone. N Engl J Med1978; 298:173-177.
- Chen S, Jalandhara N, Battle D: Evaluation and management of hyponatremia: an emerging role for vasopressin receptor antagonists. Nat Clin Pract Nephrol2007; 3:82-95.
- Dong BJ: Cinacalcet: an oral calcimimetic agent for the management of hyperparathyroidism. Clin Ther2005; 27:1725-1751.
- Arlt W, Allolio B: Adrenal insufficiency. Lancet2003; 361:1881-1893.
- Aziz NM, Oeffinger KC, Brooks S, Turoff AJ: Comprehensive long-term follow-up programs for pediatric cancer survivors. Cancer2006; 107:841-848.
- Landier W, Bhatia S, Eshelman DA, et al: Development of risk-based guidelines for pediatric cancer survivors: the Children's Oncology Group long-term follow-up guidelines from the Children's Oncology Group Late Effects Committee and Nursing Discipline. J Clin Oncol2004; 22:4979-4990.


text: Viewing commercials - 1 of 3 The Paltrow App If you like rap and you're of the Caucasian persuasion, get the Paltrow App... more »If you like rap and you're of the Caucasian persuasion, get the Paltrow App now and avoid confrontation! Notice To FOD Staff: The S&M Network would like to be considered for any and all future video production openings. « less smnetworkMatthew GeticSean Hampton June 09, 2012 93 Views More Info Full Credits smnetwork Uploader Matthew Getic Director Sean Hampton Producer Additional Credits The S&M Experience -- Season 1 Episode 3"The Paltrow App"Executive Producers: Matt Getic & Sean HamptonProducer: Eduardo BrandarizWritten by Matt Getic & Sean Hamptonin association withBen Kackley & Brendan DoolanDirected by Sean Hampton & Matthew GeticSections of this skit use music protected under the Fair Use Act. Stats & Data 8Funny0Die 93 Views June 09, 2012 Published Category Sketch Music News Fails Tags The Paltrow App Funny Commercial Apple Gwyneth actress race N-word n-bomb n**gas in Paris Jay-Z controversy Twitter tweet celeb celebrity Hollywood Kanye West (Musical Artist) language offensive Actor Famous Entertainment Singer gossip concert scoop rap hip hop Hip Hop straight outta compton NWA DMX Up Next: Black Talk Services AUTOPLAY Up Next In: 10 Black Talk Services True Motivation The Paltrow App The Hoodie Debate Follow Browse Related Comments commercials 3+ more View All ▶ 10+ more View All ▶ smnetwork 4+ more View All ▶ Matthew Getic 10+ more View All ▶ Sean Hampton Vaguely Related Videos Vaguely Related Pics & Words Advertisement Tags: The Paltrow App Funny Commercial Apple Gwyneth actress Advertisement

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text:
Let us know when your receive great advice so we can thank our lawyers and point others with similar questions in the right direction.Got it!
father passed, no will
house in his name
my mother still alive
i am the oldest of three
i live in the house and have made improvements
everyone in the family knows the house was given to me by my dad
There are some missing facts an attorney would have to know to fully answer this. These would be:
1. Was your mother and father still living at the time of his death. Or if not, was there another spouse?
2. Is your mom living in the house as well?
3. Would she be willing to transfer it into your name?
4. Would you accept the loss of property tax and capital gains benefits?
5. Would your sibliings be willing to sign away their interests?
6. Are the two other siblings also children of your parents (blood descendants)?
7. Was the house community or separate property, and/or does your mother have a constitutional life estate in the house?
8. Are (or were) there creditors or open balances of debt owed by your father at his death?
9. Did your father die with any debts owed to Medicaid?
Depending on your answers to these additional questions, there are a few possible solutions allowed by Texas law.Ask a similar question
You ( and your mother) need to sit down and go over the situation in detail with a good probate attorney. Your father's estate does need to be settled, but my guess is that the house now belongs to your mother. Good luck.
For educational purposes only. No attorney-client relationship was created by this communication.Ask a similar question
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Read: H-W Magazine
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text:
Reducing or controlling the high cost of the power to run and cool computer hardware is a top priority for many organizations throughout the world. Many organizations are considering server virtualization solutions to reduce their server footprint and the associated power and cooling costs. Because the virtualization of Microsoft Exchange servers rarely results in a reduction of physical processors, there is some question whether there is significant hardware, power, cooling, or space savings from virtualizing correctly sized Exchange Server 2007 server roles.
More info: TechNet


text:
Hike to Ribbon Falls in Grand Canyon NP
Rate this Adventure Arizona › North Kaibab Trail, Grand Canyon NP
Added by Jake Young
Hike to a secluded waterfall oasis in Grand Canyon National Park. The falls provide a wonderful juxtaposition to the hot and dry environment of the canyon.
Although this hike can feasibly done in a day, it is highly recommended that you spend more than one day in this area and visit the falls as a side trip on a larger trip. The closest campsites to Ribbon Falls are Cottonwood Campground and the Bright Angel Campground at Phantom Ranch.
Ribbon Falls is on the North Kaibab Trail which has a trailhead at the North Rim of the Grand Canyon. The trailhead is located roughly 1.5 miles from the Grand Canyon Lodge.
Ribbon Falls is a 8.4 mile hike from the North Kaibab Trailhead and 5.2 miles from Phantom Ranch. The trail loses 4521 feet from the North Rim as you pass the Supai Tunnel, Roaring Springs, Manzanita Rest Area and the Cottonwood Campground. There is seasonally available potable water at each of the previously mentioned areas.
After passing the Cottonwood Campground, look for a sign pointing to Ribbon Falls. It takes about 20 minutes to reach the falls after leaving the main trail. If approaching from the North Rim, there is a foot bridge that takes you across Bright Angel Creek. If you are approaching from Phantom Ranch, it is possible to take a spur trail that crosses the creek without the use of the bridge. However, this route should not be attempted if there has been a recent rain storm.
This hike should not be taken lightly. The total mileage of the hike is 16.8 miles with a total elevation change of 9042 feet. If you are hiking or backpacking in the summer, get an early start to avoid the peak heat of the day. Bring a large amount of water and caloric foods to ensure you don't succumb to dehydration or hyponatremia. It is also recommended to constantly soak your clothing to keep cool.
The Ribbon Falls area is a in a small canyon filled with lush vegetation. This area is an extremely fragile environment so be sure to stay on the designated trails and treat the falls with respect.
Pack List
- Water
- Food
- Sun Protection
- Photography Gear
- Water Purifier
- Tent
- Sleeping Bag
- Sleeping Pad
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Added by Jake Young
Adventurer, Photographer, Impact Investor. I work with companies that want to have a positive impact on the world around them.Follow
Chillin, Camping, Photography, Backpacking, Hiking
Skill Level:
Year Round
Trail Type:
16.8 Miles
Elev. Gain:
4521 Feet
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text:
Police from the Inner West Child Protection and Investigation Unit are reminding the public to be mindful of their responsibility when supervising their children particularly under the age of 12.
In 2016-2017, there has been more than 10 incidents reported to police in Inner West Brisbane which has resulted in six people being charged under the provisions of the Queensland Criminal Code Section 364A: Leaving a child under 12 years unattended without reasonable excuse.
If a child is left unattended, particularly in a motor vehicle, they may face unacceptable risks including heat or cold, safety and accessibility concerns.
If you have any concerns regarding a young child being left alone or unattended, please report the matter to police, Crime Stoppers on 1800 333 000, or contact the immediate venue management or security.


text:
The well proportioned luxury yacht SULARA is a motor yacht. This 33 m (108 foot) luxury yacht was produced by Camper & Nicholsons in 1924. SULARA used to be 322 Aloha; Thendara. Superyacht SULARA is a majestic yacht that is able to sleep a total of 6 passengers on board and has a total of 5 crew.
The yacht's general design work came from Charles E Nicholson. The technical naval architect firm drawings are the work of Charles E Nicholson. Created at Camper & Nicholsons the vessel was fabricated within the United Kingdom. She was officially launched in Gosport in 1924 before being transferred to the owner. The core hull was constructed with teak/oak frames. The motor yacht superstructure component is made largely from mahogany. The total length of the luxury yacht on deck is 27.43 (90 ft). With a width of 5 m or 16.4 feet SULARA has moderate size. A deep draught of 3m (9.8ft) affects the number of certain harbours she can enter into, taking into account their specific depth. She had refit maintenance and changes undertaken in 1989.
This yacht is driven by twin capable GARDNER main engine(s) and can attain a reasonable top continuous speed of approximately 12 knots. The engine of the SULARA produces 114 horse power (or 84 kilowatts). Her total HP is 228 HP and her total Kilowatts are 168. Coupled to the SULARA engines are twin screw propellers.
The well proportioned luxury yacht M/Y SULARA can accommodate as many as 6 passengers in addition to 5 qualified crew.
Her Engine(s) is two 114 Horse Power or 84 kW Gardner. Engine Model: 6L3 diesel. - Total engine power output 228 HP /168 KW. - Cruising at a speed of 11 knots. - Top Speed: 12 nautical miles per hour. - Bunkering capacity: 3600 L. - Fresh water: 4000.00. - Yacht Beam: 5m/16.4ft. - Length on Deck: 27.43m/90ft. - Waterline Length (LWL): 26.37m/86.5ft. - Draught at deepest: 3m/9.8ft.
SULARA features a teak deck.
The luxury yacht SULARA displayed on this page is merely informational and she is not necessarily available for yacht charter or for sale, nor is she represented or marketed in anyway by CharterWorld. This web page and the superyacht information contained herein is not contractual. All yacht specifications and informations are displayed in good faith but CharterWorld does not warrant or assume any legal liability or responsibility for the current accuracy, completeness, validity, or usefulness of any superyacht information and/or images displayed. All boat information is subject to change without prior notice and may not be current.
32.98m (108.2'), 1924, The United Kingdom, Camper & Nicholsons, Charles E Nicholson
Motor Yacht RioStar 160, Motor Yacht Toy Heaven (ex Fox, H.V. Fox, Ultra Plus), FOIE GRAS, Motor Yacht O'Mare , Sunseeker Predator 115 Superyacht 2010


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Known as the King of the Balagtasan and as Makata ng Puso, José Corazón de Jesús was born in Manila on November 22, 1896. He wrote Tagalog poetry during the American occupation of the Philippines (1901-1946).
His most famous work is the Tagalog poem Bayan Ko (My Country, 1929), which was used as lyrics for a patriotic song that became popular during the dictatorship of Ferdinand Marcos in the 1980s. His pen name was Huseng Batute. He died on May 26, 1932, and is buried in Manila's North Cemetery.


text:
Legal Jobs in Indiana
Find Legal and Paralegal Employment Opportunities in Indiana
Search your next legal or paralegal employment anywhere in Indiana. We offer legal job opportunities posted by legal recruiters, law firms and general employers. The search is free of charge. Our job listings are updated on a regular basis.
Indiana Legal Job Listings


text:
Eighty Four, a cosy and relaxed East London
coffee shop and restaurant. Serving up a selection of baked goods, sandwiches, salads and signature dishes each made fresh on the spot with affection using local produce where possible.
Stop in for your morning coffee & pastry. Serving Brunch, Lunch & Dinner washed down with locally roasted coffee. Try our delicious cocktails or Pint's of Camden draft beer on tap!
Drop by and check out our small (but ever expanding) collection of #Vinyl. Available to buy.
Event Space
- We are a versatile fully licensed premises with well equipped kitchen available to hire for private functions, corporate events or meet up groups.
Find out more information email: firstname.lastname@example.com
Friday nights we pick up the vibe with DJs on the decks from 6pm - 11:30.
Check out 84website: HERE
84 Great Eastern Street


text:
Agency: NUMO
Client: Tripp
Tripp, the exclusive retailer of luggage to Debenhams, has launched a campaign to promote two new ranges of luggage in Ireland.
The three month campaign aims to raise awareness of John Rocha's new Punch Work Collection, a seven piece signature range in John Rocha's black and taupe colours.
The campaign also sets out to promote the latest travel range from Orla Kiely, a unique and instantly recognisable set featuring wheeled suitcases, hand luggage, laptop cases and a vanity case.
The campaign has been planned and created in the UK by digital media agency, NUMO Group, and involves PR and digital advertising across two of Ireland's largest media platforms, the Irish Times and RTE.
The objective of the campaign is to drive traffic to Tripp's new website trippluggage.ie and to capture data in new market segments from a series of online competitions. "Tripp only entered the Irish market in the last few months, so this campaign will play a vital role in increasing the brand's visibility amongst a key ABC1 target audience" says Steve Tomkinson, director of NUMO.
Steve continued, "We are confident that Tripp's target audience will get plenty of opportunity to see the brand and take part in our competition to win some of the most exclusive luggage ranges on the market."
Each month of the campaign, competition entrants get the chance to win up to €700 worth of luxury designer luggage from both John Rocha's Punch Work Collection and the new range of Orla Kiely luggage.
3073 showcases match your criteria
Editor's pick - The Sun's campaign
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50% recommend it
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View add here
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See ad here
Editor's pick - Go Compare guy gets what's been coming to him
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Editor's Pick - Phones 4u's "Upgrades 4 u and u"
See it here
Editor's Pick - McDonald's Euro 2012-themed Championship Menu
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Editor's Pick - M&M's ad celebrates Queen's Diamond Jubilee
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67% recommend it
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text:
found a new home!
Plenty of my friends are looking
for one too. Find a pet to adopt.
Rocket: Microchipped, Spayed Female, White & Gray
Nibbles: Microchipped, Neutered Male, White
Age: 3.5 years
Nibbles is very protective of Rocket and isn't a huge fan of petting. Nibbles also does the cutest snoring when he sleeps!
Rocket loves attention. And is a very sweet bunny.
They would prefer to be adopted together, but can be adopted separately if you only want one bunny.
You can meet them during store hours at
34900 Monterey
Palm Desert, CA 92211
Come meet them today.
Rocket & Nibbles, a Palm Desert Other/Unknown was adopted! Here's how you can benefit by looking at adoption as an option to buying a Other/Unknown for sale in Palm Desert, or seeking a Other/Unknown from a breeder in Palm Desert.


text:
Research topics
In the Workspace Innovation Lab, we study the effects of different environmental situations and working practices on the performance, motivation, and well-being of office and knowledge workers. The main factors affecting workers are as follows:
- Environmental conditions in the workplace, such as lighting, air quality, acoustics, design, etc.
- Information and communication technologies, e.g. tools and equipment for adaptable workstations
- Organization; above all, flexible working times and locations
- Work requirements such as tasks, concentration, communication, etc.
- Individual lifestyle
In this laboratory, different spatial and technological working situations and environments as they exist in office buildings today and above all in the future (for work that involves talking to others vs. working in silence, working alone vs. project work, etc.) are tangibly demonstrated in conjunction with multi-location working scenarios (working from home, while on the move, in a co-working center, on the customer's premises, etc.). The Workspace Innovation Lab is designed to be a lived-in laboratory, where the latest questions, concepts, and products relating to office and knowledge work are investigated, evaluated, and developed in concrete usage contexts. This experimental platform allows researchers to model and study virtually all aspects of a workplace with flexible working times and locations.


text:
Guardian deputy editor Paul Johnson has been promoted to the newly created role of head of news, business and sport.
Johnson will oversee plans for further news team integration across the Guardian, Observer and guardian.co.uk website.
Guardian editor Alan Rusbridger remains editor in chief of the Guardian News & Media Group (GNM), which publishes all three publications, and John Mulholland and Emily Bell remain as the editors of the Observer and guardian.co.uk respectively.
Four new heads of national news, business, sport and international news will be appointed to work across all three titles at a later date.
The changes come as GNM prepares to move to a new North London base in November.
[lnk|http://www.featuresexec.com/publications/info_features.php?pubid=332|_self|The Guardian]
[lnk|http://www.featuresexec.com/publications/info_features.php?pubid=393|_self|The Observer]
[lnk|http://www.featuresexec.com/publications/info_features.php?pubid=6923|_self|Guardian Unlimited]


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22 comments
Holy shit I love this. veeeeeeeeeerrrry rich sounds ty dude
Will use this in a 4th of July video clip. Thank you!
no sound in it
Thanks! For a little strokable robot I'm making...
what kind of instruments were used?
unfortunately i do not understand any vietnamese. the words were coming through a public address system, though, so i assume it's some kind of municipal broadcast from city or state authorities
Another Goody!
Fantastic Sound!
Thanks for this, I used it in a space-based puzzle game I made: https://play.google.com/store/apps/details?id=com.everless.gravital
It was helpful.
Thank you.
It's brilliant and exactly what I needed, thank you!
Could you tell us any more about what's being said?
this sound has everything. Thanks!
These are some noisy birds! I wonder what they are trying to communicate to each other. I lived in New Hampshire when I was a boy, so I especially appreciated your recording. Thanks!
thank you
Thanks; this will be helping to depict the brain's electrical processes in sound!
Sweet sound.
22 comments


text:
The Moistest Chocolate Cake You'll Ever Make
READY IN: 35mins
Recipe by Grace4Gayle
This is no ordinary dry chocolate cake. It's so moist that it doesn't even need frosting and is even better and more moist the second day. Has a nice spongy texture but I can almost guarantee you won't have any leftovers. Plus it has no complicated ingredients and can be made all in one bowl. The recipe was passed down from my grandmother to my mom and was originally called Cheapcake because of it's lack of milk or eggs.
Ingredients Nutrition
- 1 1⁄2 cups flour
- 1 cup sugar
- 1 teaspoon salt
- 1 teaspoon baking soda
- 1 cup water
- 1 teaspoon vanilla
- 1 teaspoon vinegar
- 4 teaspoons cocoa
- 6 tablespoons oil or 6 tablespoons melted butter
Directions See How It's Made
- Put all ingredients in bowl and stir or use mixer until completely combined.
- Bake in a greased 9 inch square pan at 350 degrees for 30 minutes or until toothpick inserted in center comes out clean.


text: Although the cause of MS is unknown, it is widely considered to be an autoimmune disease in which the person's immune system attacks the brain and/or spinal cord, the FDA says. Tysabri appears to work by binding to these immune system cells, thus preventing them from traveling to the brain where they can cause damage. In the first clinical trial of the product's safety and efficacy, the drug reduced the frequency of relapses by 66% relative to placebo, the FDA announcement said. In another clinical trial, patients who had been treated with Biogen's MS drug Avonex but who had experienced one or more relapses while on Avonex were given either Tysabri or placebo. Avonex was continued throughout the study for both groups. In this trial, Tysabri reduced the frequency of relapses by 54% relative to placebo. For Biogen Idec, the big question is whether -- or by how much -- Tysabri will cannibalize sales of Avonex. Analysts have said they expect Tysabri to perform well at the expense of other MS drugs, including Rebif from Serono ( SRA); Betaseron from Chiron ( CHIR); and Copaxone from Teva Pharmaceutical Industries ( TEVA).


text:
Call Us Toll Free
Email Us
Customer Services
Call Us Toll Free
Email Us
Customer Services
40% off
Was $160.00 Now $96.00
Versatile enough for off-duty days and evenings out, our ankle-zip pants bring a sporty aesthetic to everyday looks. Designed with invisible zips to the inside of the ankles, these have a flattering flat front and elasticated waistband to the back, making comfort key. Tuck in a cotton T-shirt and then dress them up with vertiginous sandals, or opt for sneakers on weekends.
Flat front with drawstring
Elasticated waist panel at back
100% polyester
STANDARD NON-TRACKABLE SHIPPING - $9.95 (unless a promotion has been applied) Please allow 6-10 business days for delivery. May require a signature.
STANDARD TRACKABLE SHIPPING - $13.95 (unless a promotion has been applied) Please allow 5-9 business days for delivery. May require a signature.
EXPRESS SHIPPING - $35.95 Please allow up to 4 business days for delivery. Order by 12pm EST Monday to receive by Friday. May require a signature.
SHIPPING OUTSIDE THE US - Please allow 14 business days for delivery. Click here for International shipping charges
Please select your preferred shipping option at checkout
The White Company pays all import taxes and duties on your behalf.
More shipping information including charges
Returns – FREE (for the US) – Smart label returns are convenient and easy.
Click here for more returns information, including smart returns labels
Just tick the gift-box option during checkout to make it even more special.
FREE standard delivery on orders over £50 (usually £4.95). For next day delivery, order before midday (£7.95).
Our delivery rates to Europe start from £7 and usually take 5 - 7 working days. If ordering from the US (rates from £15) or Australia (rates from £20), please allow 10 - 14 days for delivery.


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Whether you're increasing, decreasing, or cancelling your patronage, let me first say Thank You! for whatever level of patronage you've supported me with.
Here's how you change it.
Patronage and payments for patronage are all handled by Patreon.com. You'll have created an account with Patreon when you set up your patronage to start.
So, step one is to visit patreon.com and log in to your account.
Once there, hover your mouse over the icon in the upper right and a drop-down menu will appear.
Click on Your Pledges to be taken to a list of the various creators that you may be supporting on Patreon.
Click on the Edit Pledge link on the Ask Leo! line.
To change your pledge
Click on Edit next to "Your pledge to Ask Leo!". On the following page (not shown) you'll be able to select a new reward, and specify a new amount. (The minimum is $1, available if you pick "No reward".) You'll then be returned to this page, where you then click Save Changes to apply the new patronage amount.
To cancel your pledge
Click on the grey Delete Pledge underneath the Save Changes button. You'll be asked to confirm (not shown), after which your pledge will be immediately deleted. You'll then be asked why you elected to delete your pledge; this step is entirely optional.
All changes to payments take effect on the first of the immediately following month, when patrons are charged.
If your rewards level changes in any way, we'll take care of that within a day or two of your change.
And again, thank you very much for yoru patronage!


text:
Langston Hughes
February 1st, 1902 - May 22nd, 1967
Hold fast to dreams
For if dreams die
Life is a broken-winged bird
That cannot fly.
Hold fast to dreams
For when dreams go
Life is a barren field
Frozen with snow.
As a child in Joplin, Missouri, Mr. Hughes lived with his grandmother. His parents were divorced, and his father had left to Mexico to escape racism. After the death of his grandmother, he went to highschool. He was elected class poet. He wrote that his classes reasoning for electing him was because "Blacks have rhythm". It was there he wrote his first poems.
By 1925, Hughes' poems were being collected into his first poetry book. His poem Weary Blues won first place in Opportunity magazine in 1926. He received a scholarship from Lincoln University, where he met Carl Van Vechten, who helped him get his book published. It gained interest due to his jazz-esque poetry style and African American themes. His second book was published in 1927. After graduating, he released a novel, which earned him enough to convince him to become a writer. He died on May 22nd, 1967.


text:
Get an overview of this hotelHistoric hotel with free breakfast and free valet parking
Popular property highlights
Situated in Adarsh Nagar, this historic hotel is within a 15-minute walk of Museum of Indology, Central Museum, and Ram Niwas Gardens. Bapu Bazaar and Johri Bazaar are also within 1 mi (2 km).
Hotel Features
This hotel features a restaurant, an outdoor pool, and a health club. Free buffet breakfast is provided, as well as free WiFi in public areas, free valet parking, and free train station pick-up. Other amenities include a bar/lounge, 24-hour room service, and concierge services.
Room Amenities
All 15 individually decorated rooms feature free WiFi and 24-hour room service. Guests can enjoy deep soaking tubs, and other standard amenities include premium bedding and satellite TV.Information missing or incorrect? Tell us!Opens in a new window
Naila Bagh Palace
Hotel Amenities
Hotel Amenities
Naila Bagh Palace features an outdoor pool and a health club. The hotel offers a restaurant. A bar/lounge is on site where guests can unwind with a drink. Guests can enjoy a complimentary breakfast each morning. A computer station is located on site and wireless Internet access is complimentary.
This Art Deco hotel also offers tour/ticket assistance, barbecue grills, and gift shops/newsstands. For a surcharge, the property provides a roundtrip airport shuttle (available on request) and a train station pick-up service. Complimentary self parking and valet parking are available on site.
- 24-hour front desk
- Airport transportation (surcharge)
- Free breakfast
- Concierge services
- Hair salon
- Total number of rooms - 15
- Limo or Town Car service available
- Number of floors - 1
- Free valet parking
- Babysitting or childcare
- Porter/bellhop
- Luggage storage
- Restaurant
- Free train station pickup
- Train station pickup (surcharge)
- Free self parking
- Bar/lounge
- Barbecue grill(s)
- Free newspapers in lobby
- Dry cleaning/laundry service
- Express check-in
- Express check-out
- Gift shops or newsstand
- Health club
- Pool umbrellas
- Billiards or pool table
- Tours/ticket assistance
- Free WiFi
- Computer station
- Laundry facilities
- Garden
- Picnic area
- Safe-deposit box at front desk
- Year Built 1870
- Shopping on site
- Number of buildings/towers - 2
- Outdoor pool
- Wedding services
Family Friendly Amenities
- Family Hotel
- Outdoor pool
- Free Wi-Fi
- Rollaway/extra beds available
- Laundry facilities
- Babysitting or childcare
Available in all rooms: Free WiFi
Available in some public areas: Free WiFi
Free self parking, Free valet parking
Room Amenities
- Premium TV channels
- Air conditioning
- Bathrobes
- Hair dryer (on request)
- In-room safe
- Rollaway/extra beds available
- Cribs/infant beds available
- Hypo-allergenic bedding available
- Premium bedding
- Ceiling fan
- Phone
- Free bottled water
- Daily housekeeping
- Turndown service
- Private bathroom
- Free toiletries
- Deep soaking bathtub
- Bathtub or shower
- Room service (24 hours)
- Desk
- Iron/ironing board (on request)
- Satellite TV service
- Free WiFi
- Individually furnished
- Individually decorated
Where to Eat
Guests are offered a complimentary buffet breakfast each morning.
Pool side - Overlooking the pool and garden, this restaurant serves lunch and dinner. Guests can enjoy drinks at the bar.
24-hour room service is available.
Nearby Things to Do
Recreational amenities at the hotel include an outdoor pool and a health club.
The recreational activities listed below are available either on site or nearby; fees may apply.
- Golfing nearby
- Basketball on site
Spa Services
- Ayurvedic treatments
Hotel Policies
Minimum check-in age is 18
Check-in time starts at noon
Special check-in instructions:
Check-out time is noon
Payment types
Children and extra beds
- Children are welcome.
- Kids stay free! Children 6 years old and younger stay free when using existing bedding.
- Rollaway/extra beds are available.
- Cribs (infant beds) are available.
- No pets or service animals allowed
You need to know
Extra-person charges may apply and vary depending on property policy.
- Christmas Eve (24 December) Gala Dinner per adult: INR 2500
- New Year's Eve (31 December) Gala Dinner per adult: INR 2500
Optional extras
- Airport shuttle fee: INR 750 per vehicle (one way)
Hotel Name
- Naila Bagh
- Naila Bagh Palace
- Naila Bagh Palace Hotel
- Naila Bagh Palace Hotel Jaipur
- Naila Bagh Palace Jaipur
- Naila Palace
- Naila Bagh Palace - Authentic Heritage Home Hotel Hotel Jaipur
We should mention
Reservations are required for massage services and spa treatments. Reservations can be made by contacting the hotel prior to arrival, using the contact information on the booking confirmation. Children 6 years old and younger stay free when occupying the parent or guardian's room, using existing bedding. No pets and no service animals are allowed at this property.
Awards & Affiliations
- The property is a member of Heritage Hotels of India.


text:
Echoes is a Star Wars: The Old Republic guild.
About the guild
Echoes are a multi gaming community that started in 2004 in Star Wars Galaxies on the Chimaera server.
We are now waiting for the release of The old Republic to continue our adventures.
Joining the guild
We are a casual guild with mainly EU members playing on an EU server. If you are looking for a friendly, fun loving and helpful guild you have come to the right place. We prefer easygoing mature players who are able to find their own fun in the game and do not expect guild leaders to do it for them.


text:
|Yosemite Dual Sport Adventure
September 23rd & 24th, 2017 (Weekend Event)
Download the Waiver of Liability
Event Description:
The Yosemite Dual Sport Adventure is an AMA Sanctioned dual sport event held at the gateway to Yosemite National Park in Buck Meadows and is open to any make or model of street legal motorcycle.
This two day, GPS based, self-guided adventure includes scenic & historic destinations both in and around Yosemite National Park and the Stanislaus National Forest. Using paved and unpaved roads with options of "hard" & "easy" splits, you'll have approximately 100 miles of fun each day! "Easy" routes are perfect for beginning riders or large adventure bikes. Experienced riders can be challenged by choosing "hard" splits. We do our best to include as many dirt routes as possible.
Event is operated under permit from the Stanislaus National Forest and limited to 150 riders so register early! This event caters to ALL street legal dual sport motorcycles.
One day tickets are available. Passengers are half-price. 150 rider limit so register early! AMA requires all riders to be AMA members. Please get your AMA membership here: www.amajoin.com/faorad.
[GPS: N37 48.926 W120 03.765] From Highway 99 or Interstate 5 take the Highway 120 exit East towards Yosemite. Stay on Highway 120 for 65 miles till you arrive in the town of Groveland. Buck Meadows is a small community about 11 miles East of Groveland, towards Yosemite. (Click Here for MAP).
Our host for this event is the small and historic community of Buck Meadows. Within this community is the Yosemite Ridge Resort http://www.yosemiteridge.com/ They can be reached at 800-706-3009 and provide cabins, full RV hookups, gas station, general sore & local dining. The "Yosemite Westgate Motel" (typical "Motel 6" style) is also in Buck Meadows and the nearby are "Lost Claim" or "The Pines" campground operated by the Stanislaus Nation Forest. Additional accommodations are available in Groveland.
Registration & Staging Location:
Meet us at the registration booth to pick up your packet starting Friday at 5pm and resume again at 8:00am Saturday Morning. Our booth & staging location is on the grass next to the general store and fuel pumps in Buck Meadows.
FREE GPS Training:
There will be a FREE class on how to navigate with GPS while riding in the back-country. With or without trails, roads, land-marks or a paper map you'll be able to confidently navigate anywhere on the planet once you know the ropes. Bring your GPS pre-loaded with our routes, something to take notes on and an open mind. This class will be at 6:30pm on Friday at the registration tent.
Fundraising BBQ & Raffle:
Join us on Saturday at 7pm! THOUSANDS of dollars in gear, parts, accessories & apparel for you to win! Food, Prizes & Fun! Get your BBQ tickets on-line now. BBQ funds benefit Tuolumne Trails which helps kids with special needs enjoy the outdoors. Funds generated from the raffle are donated to Blue Ribbon Coalition.
GPS Routing:
Bring your GPS!!! A download of suggested routes and destination will be emailed to you a few days before your adventure. Suggested routes will consist of limited pavement, gravel and dirt roads. Each day is usually about 100 miles, visiting different destinations each day. We do our best to use dirt routes as much as possible. If registering at the event, bring your GPS download cable.
Scenic Rides:
THIS IS NOT A RACE!!! This is a fun, EZ-to-follow, on/off-road, leisurely, scenic and historic trip through parts of the beautiful Stanislaus National Forest and Yosemite National Park. In most cases easy routes are passable with a 4WD vehicle. In case routes or destinations are closed alternate destinations and routes will be selected.
Motorcycle Requirements:
All motorcycles must meet the following requirements. Failure to meet ALL requirements will result in your money being refunded and you being asked to leave the event.
Other Information:
17:00 Sign-up booth open
18:30 FREE GPS training @ sign-up booth
08:00 Sign-up booth open - Vendor booths open
08:15 Pre-ride meeting @ registration booth
08:30 First bikes out
09:00 Last bikes out
~ 11:30 Lunch is available
~ 14:00 All bikes leave lunch stop
19:00 Optional fundraising BBQ, Raffle Prizes, Awards & Recognize Sponsors
08:00 Sign-up booth open - Vendor booths open
08:15 Pre-ride meeting @ registration booth
08:30 First bikes out
09:00 Last bikes out
11:30 Lunch available
14:00 Lunch ends - All bikes depart lunch stop


text:
Lilly Ledbetter Fair Pay Act of 2009 -- (House of Representatives - January 9, 2009)
Madam Speaker, I rise in strong support of the H.R. 11, the Lilly Ledbetter Fair Pay Act of 2009.
For nearly 20 years, Lilly Ledbetter worked at a Goodyear Tire facility in Alabama. After learning that she was the lowest paid supervisor--earning 20 percent less than the lowest paid, least experienced man in the same position at Goodyear--she sued the company for pay discrimination. On May 29, 2007, after a series of cases and appeals, the Supreme Court handed down a disturbing 5-4 ruling that fundamentally rewrote protections that American workers have enjoyed for more than 40 years when they were codified in the Civil Rights Act of 1964.
According to Justice Samuel Alito, who wrote the flawed decision, when Ms. Ledbetter failed to file a discrimination case within the statutorily provided 180 days from the initial decision to pay her less than her male colleagues, she was barred from filing a complaint and no relief was available. Despite documenting the sex based evaluation system Goodyear managers used, Lilly Ledbetter was denied justice and the rights afforded to her under the Civil Rights Act.
Justice Alito's opinion runs contrary to decades of civil rights law, and the Lilly Ledbetter Fair Act would restore the law as it was prior to the Court's ill considered decision. This bill would make it clear that when it comes to discriminatory pay, the protections of Title VII of the Civil Rights Act, the Age Discrimination in Employment Act, the Americans with Disabilities Act and the Rehabilitation Act extend not only to these discriminatory pay decisions and practices but to every paycheck that results from those pay decisions and practices.
As an original cosponsor of the Lilly Ledbetter Fair Pay Act, I urge my colleagues to support its passage, and I encourage the Senate to work quickly to send it to the President.
Source: http://thomas.loc.gov


text:
- Trending Now: More Trending:
- hegemon repugnant white nationalist, white supremacist bereft impanel
go/run through someone's mind
Definition of go/run through someone's mind
: to be what someone is thinking about What was going/running through your mind when you agreed to do this?
Word by Word Definitions
: to move on a course : proceed — compare stop
: to move out of or away from a place expressed or implied : leave, depart
: to take a certain course or follow a certain procedure
: the act or manner of going
: the height of fashion : rage
: an often unexpected turn of affairs : occurrence
: functioning properly : being in good and ready condition
: a game played between two players who alternately place black and white stones on a board checkered by 19 vertical lines and 19 horizontal lines in an attempt to enclose the larger area on the board
: to go faster than a walk
: to go steadily by springing steps so that both feet leave the ground for an instant in each step
: to move at a fast gallop
: an act or the action of running : continued rapid movement
: a quickened gallop
: a migration of fish (as up or down a river) especially to spawn
: being in a melted state
: made from molten material : cast in a mold
: having made a migration or spawning run
: some person : somebody
: recollection, memory
: the element or complex (see 1complex 1) of elements in an individual that feels, perceives, thinks, wills, and especially reasons
: the conscious mental events and capabilities in an organism
: remind
: remember
: to attend to closely
Seen and Heard
What made you want to look up go/run through someone's mind? Please tell us where you read or heard it (including the quote, if possible).


text:
This week Mac was awarded a Pride of Australia Medal. You can read all about here.
This is McKenzie J. Gregory, Melbourne Australia. He's 89, a WW2 veteran, retired from the Royal Australian Navy, aide-de-camp to several Australian prime ministers. Now a naval historian Mac honors the sacrifices of Australia's naval forces mostly though his blog.
We met by chance on the web. We've been blogging together for 10 years on Ahoy - Mac's Web Log. Mac writes; I put it on the web. We've published more than a million words. It's been my privilege and honor.
We've never met though we've talked on the phone a couple times. None-the-less I regard him as family.
So I'm delighted that Mac is now on Youtube accepting and commenting on the award.
Congratulation Mac!
Friday, August 26, 2011
Mac earns another medal, my bloggong partner for 10 years.
Labels: personal
3 comments:
Wow, Terry, a whole new side I've never known about you. I will play the video post haste, I think it is fab how you lend a hand as you do, you are the best. Now - on to learn about your wonderful friend.ReplyDelete
I just viewed the video and perused his extensive site, good heavens what a lot of information and work has gone into this beautiful man's blog! Kudos to you for your assistance~ I think it is such an important site, historically, and helping others. I wish to go back and read a lot more on his life.ReplyDelete
Further proof that friends and family come in many different forms. Thanks for remind us of that, Terry, and congratulations to Mr. Gregory.ReplyDelete
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- Yellow Morningside Poptop. Teardown week.
- Missing on Maryland Ave. Teardown week
- Hippie Shed Attic is a goner. Teardown week.
- This is a goner. Teardown week.
- Four Coats Mural #4 by Sunday Southern Art Revival...
- Four Coats Mural #3 by Andy Moon Wilson
- Four Coats Mural #2 by Lucha Rodriguez:
- Four Coats, Mural #1 by Tommy Taylor
- I got "5 questioned" and blogged by Jon Effron
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