Outcomes of Indeterminate Thyroid Nodules Managed Nonoperatively after Molecular Testing.

CONTEXT: Molecular testing to refine the diagnosis of cytologically indeterminate thyroid nodules has become increasingly popular, but data on long-term durability of test results and the rate of delayed operation are limited. OBJECTIVE: Determine the delayed rate of surgical resection in indeterminate nodules with benign/negative molecular testing and the risk of false-negative molecular test results. DESIGN: Prospective follow-up of the Gene Expression Classifier vs Targeted Next-Generation Sequencing in the Management of Indeterminate Thyroid Nodules randomized controlled trial comparing the diagnostic test performance of Afirma Gene Expression Classifier and ThyroSeq v2. SETTING: University of California, Los Angeles. PARTICIPANTS: Patients who underwent thyroid biopsy with indeterminate (Bethesda III/IV) cytology (April 2016 to July 2017). INTERVENTION: Ultrasound surveillance. MAIN OUTCOME MEASURE: False-negative rate of molecular testing. RESULTS: Of 95 indeterminate nodules with negative/benign molecular test results, 12 nodules underwent immediate resection (11 benign nodules, 1 noninvasive follicular thyroid neoplasm nodule with papillary-like nuclear features). Nonoperative management was pursued for 83 (87.4%) nodules. The median surveillance was 26.7 months. Ten nodules were resected during surveillance and malignancy was identified in 4 nodules (overall false-negative rate of 5.8%). In the 4 malignant nodules that underwent delayed operation, surgery was prompted by sonographic changes during surveillance. CONCLUSIONS: The majority of indeterminate nodules with negative molecular testing have a stable clinical course over 3 years of follow-up, but our finding of a 6% false-negative rate highlights the importance of continuing sonographic surveillance. Long-term studies are needed to determine the optimal length of follow-up.

Sudden Cardiac Arrest in a Patient With Myxedema Coma and COVID-19.

SARS-CoV-2 infection is associated with significant lung and cardiac morbidity but there is a limited understanding of the endocrine manifestations of coronavirus disease 2019 (COVID-19). Although thyrotoxicosis due to subacute thyroiditis has been reported in COVID-19, it is unknown whether SARS-CoV-2 infection can also lead to decompensated hypothyroidism. We present the first case of myxedema coma (MC) in COVID-19 and we discuss how SARS-CoV-2 may have precipitated multiorgan damage and sudden cardiac arrest in our patient. A 69-year-old woman with a history of small cell lung cancer presented with hypothermia, hypotension, decreased respiratory rate, and a Glasgow Coma Scale score of 5. The patient was intubated and administered vasopressors. Laboratory investigation showed elevated thyrotropin, very low free thyroxine, elevated thyroid peroxidase antibody, and markedly elevated inflammatory markers. SARS-CoV-2 test was positive. Computed tomography showed pulmonary embolism and peripheral ground-glass opacities in the lungs. The patient was diagnosed with myxedema coma with concomitant COVID-19. While treatment with intravenous hydrocortisone and levothyroxine were begun the patient developed a junctional escape rhythm. Eight minutes later, the patient became pulseless and was eventually resuscitated. Echocardiogram following the arrest showed evidence of right heart dysfunction. She died 2 days later of multiorgan failure. This is the first report of SARS-CoV-2 infection with MC. Sudden cardiac arrest likely resulted from the presence of viral pneumonia, cardiac arrhythmia, pulmonary emboli, and MC-all of which were associated with the patient's SARS-CoV-2 infection.

Antibody-Mediated Extreme Insulin Resistance: The Importance of Pre-Treatment Screening.

We report the case of a 56 year-old Hispanic male with a 10-year history of type 2 diabetes who presented with abrupt onset of hyperglycemia resistant to escalating doses of intravenous insulin infusion (>2500 units daily). He was diagnosed with antibody-mediated insulin resistance given the presence of hyperglycemia despite receiving >200 units insulin/day, a lack of identifiable precipitants for diabetic ketoacidosis or hyperosmolar hyperglycemic state, and elevated insulin antibodies. He underwent pre-immunomodulatory therapy screening for infections, rheumatologic disorders, and malignancy, which uncovered a new diagnosis of latent tuberculosis. While concurrently being treated for latent tuberculosis, he successfully responded to immunomodulatory therapy with rituximab, dexamethasone, and cyclophosphamide. Insulin was discontinued completely, and he maintained appropriate glycemic control on oral diabetic agents (metformin and pioglitazone). This case supports the use of immunomodulatory therapy for the treatment of antibody-mediated insulin resistance and highlights the importance of pre-immunomodulatory therapy screening to uncover occult infection or identify underlying neoplastic/rheumatologic disease prior to immunosuppression.

Associations Between Change in Total and Free 25-Hydroxyvitamin D With 24,25-Dihydroxyvitamin D and Parathyroid Hormone.

Context: The physiologic role of free 25-hydroxyvitamin D [25(OH)D] in humans is unclear. Objective: To assess whether rise in total vs free 25(OH)D is associated with change in downstream biomarkers of 25(OH)D entry into target cells in kidney and parathyroid: 24,25-dihyroxyvitamin D [24,25(OH)2D] and PTH, respectively. Design: 16-week randomized controlled trial. Intervention: 60 µg (2400 IU)/d of D3 or 20 µg/d of 25(OH)D3. Setting: Academic medical center. Participants: 35 adults age ≥18 years with 25(OH)D levels < 20 ng/mL. Main Outcome Measures: 24,25(OH)2D, 1,25-dihyroxyvitamin D [1,25(OH)2D] and PTH. Results: At baseline, participants [D3 and 25(OH)D3 groups combined] were 35.1 ± 10.6 years. Mean total 25(OH)D, free 25(OH)D, 24,25(OH)2D, and PTH were 16.6 ng/mL, 4.6 pg/mL, 1.3 ng/mL, and 37.2 pg/mL, respectively. From 0 to 4 weeks, rise in only free 25(OH)D was associated with a concurrent 24,25(OH)2D increase [P = 0.03, adjusted for change in 1,25(OH)2D and supplementation regimen] and PTH decrease (P = 0.01, adjusted for change in calcium and supplementation regimen). Between 4 and 8 weeks, and again from 8 to 16 weeks, rises in free and total 25(OH)D were associated with 24,25(OH)2D increase; in contrast, rise in neither total nor free 25(OH)D was associated with PTH decrease during these time periods. Conclusions: Early rise in free 25(OH)D during treatment of vitamin D deficiency was more strongly associated with changes in biomarkers of 25(OH)D entry into target kidney and parathyroid cells, suggesting a physiologic role of free 25(OH)D in humans.

Subclinical Hyperthyroidism: When to Consider Treatment.

Subclinical hyperthyroidism is defined by a low or undetectable serum thyroid-stimulating hormone level, with normal free thyroxine and total or free triiodothyronine levels. It can be caused by increased endogenous production of thyroid hormone (e.g., in Graves disease, toxic nodular goiter, or transient thyroiditis), by administration of thyroid hormone to treat malignant thyroid disease, or by unintentional excessive replacement therapy. The prevalence of subclinical hyperthyroidism in the general population is about 1% to 2%; however, it may be higher in iodinedeficient areas. The rate of progression to overt hyperthyroidism is higher in persons with thyroid-stimulating hormone levels less than 0.1 mIU per L than in persons with low but detectable thyroid-stimulating hormone levels. Subclinical hyperthyroidism is associated with an increased risk of atrial fibrillation and heart failure in older adults, increased cardiovascular and all-cause mortality, and decreased bone mineral density and increased bone fracture risk in postmenopausal women. However, the effectiveness of treatment in preventing these conditions is unclear. A possible association between subclinical hyperthyroidism and quality-of-life parameters and cognition is controversial. The U.S. Preventive Services Task Force found insufficient evidence to assess the balance of benefits and harms of screening for thyroid dysfunction in asymptomatic persons. The American Thyroid Association and the American Association of Clinical Endocrinologists recommend treating patients with thyroid-stimulating hormone levels less than 0.1 mIU per L if they are older than 65 years or have comorbidities such as heart disease or osteoporosis.

Thyroid hormone treatment activates protective pathways in both in vivo and in vitro models of neuronal injury.

Thyroid hormone plays an important role in brain development and adult brain function, and may influence neuronal recovery after Traumatic Brain Injury (TBI). We utilized both animal and cell culture models to determine the effects of thyroid hormone treatment, post TBI or during hypoxia, on genes important for neuronal survival and neurogenesis. We show that TBI in rats is associated with a reduction in serum thyroxine (T4) and triiodothyronine (T3). A single dose of levothyroxine (T4), one hour after injury, increased serum T4 and normalized serum T3 levels. Expression of genes important for thyroid hormone action in the brain, MCT8 and Type 2 deiodinase (Dio2) mRNA, diminished after injury, but were partially restored with T4 treatment. mRNA from the Type 3 deiodinase (Dio3) gene, which inactivates T4 to reverse T3 (rT3), was induced 2.7 fold by TBI, and further stimulated 6.7-fold by T4 treatment. T4 treatment significantly increased the expression of mRNA from Bcl2, VEGFA, Sox2 and neurotrophin, genes important for neuronal survival and recovery. The cortex, compared to the hippocampus and cerebellum, sustained the greatest injury and had the most significant change in gene expression as a result of injury and the greatest response to T4 treatment. We utilized hypoxia to study the effect of neuronal injury in vitro. Neuroblastoma cells were exposed to reduced oxygen tension, 0.2%, and were compared to cells grown at control oxygen levels of 21%. T3 treatment significantly increased hypoxia inducible factor (HIF)-2α protein, but not HIF-1α. In a hypoxia time course exposure, expression of hypoxia-mediated genes (VEGF, Enolase, HIF2α, c-Jun) peaked at least 8 h earlier with T3-treatment, compared to cells grown without T3. The early induction of these genes may promote cellular growth after injury. After hypoxic injury, T3 induced mRNA expression of the genes, KLF9 and hairless, important for T3-mediated brain function. The findings from both in vitro and in vivo studies support a role of thyroid hormone in activating pathways important for neuronal protection and promotion of neuronal recovery after injury.

LYMPHOCYTIC THYROIDITIS IS ASSOCIATED WITH INCREASED NUMBER OF BENIGN CERVICAL NODES AND FEWER CENTRAL NECK COMPARTMENT METASTATIC LYMPH NODES IN PATIENTS WITH DIFFERENTIATED THYROID CANCER.

OBJECTIVE: Whether or not autoimmune thyroid disease influences the progression of differentiated thyroid cancer (DTC) remains controversial. Findings of previous studies are influenced by lead time bias and/or procedure bias selection. These biases can be reduced by studying a single-institution patient population that underwent a similar extent of surgical resection. METHODS: From a cohort of 660 patients with DTC who underwent thyroidectomy, we retrospectively studied 357 patients who underwent total thyroidectomy and central compartment node dissection (CCND) for DTC between 2003 and 2013. RESULTS: Forty-one percent (140/345) of study patients had lymphocytic thyroiditis (LT), and 30% (91/301) had serum positive for thyroglobulin antibody (TgAb). LT was reported in 78% of the TgAb-positive cases. Sixty percent (213/357) of cases had metastatic thyroid carcinoma in 1 or more neck lymph nodes (55% [198/357] central compartment, and 22% [77/356] lateral compartment). Patients with LT had fewer metastatic cervical lymph nodes than those with no LT (2.7 ± 4.7 vs 3.5 ± 4.8, respectively, P = .0285). Patients with positive TgAb and thyroiditis had a larger number of benign cervical lymph nodes removed than those with negative TgAb or no LT. No significant difference was observed in age, tumor size, multifocality, extrathyroidal extension, vascular invasion, or frequency of cervical lymph node metastasis between TgAb-negative and -positive cases or between cases with and without LT. CONCLUSION: Lymphocytic thyroiditis is associated with fewer central neck compartment metastatic lymph nodes and a larger number of excised reactive benign cervical lymph nodes. Whether this association indicates a protective role of thyroid autoimmunity in lymph node spreading remains unclear. ABBREVIATIONS: CCND = central compartment node dissection DTC = differentiated thyroid cancer HT = Hashimoto thyroiditis LT = lymphocytic thyroiditis TgAb = thyroglobulin antibody TPO = thyroid peroxidase.

Sca1⁺ murine pituitary adenoma cells show tumor-growth advantage.

The role of tumor stem cells in benign tumors such as pituitary adenomas remains unclear. In this study, we investigated whether the cells within pituitary adenomas that spontaneously develop in Rb+/- mice are hierarchically distributed with a subset being responsible for tumor growth. Cells derived directly from such tumors grew as spheres in serum-free culture medium supplemented with epidermal growth factor and basic fibroblast growth factor. Some cells within growing pituitary tumor spheres (PTS) expressed common stem cell markers (Sca1, Sox2, Nestin, and CD133), but were devoid of hormone-positive differentiated cells. Under subsequent differentiating conditions (matrigel-coated growth surface), PTS expressed all six pituitary hormones. We next searched for specific markers of the stem cell population and isolated a Sca1(+) cell population that showed increased sphere formation potential, lower mRNA hormone expression, higher expression of stem cell markers (Notch1, Sox2, and Nestin), and increased proliferation rates. When transplanted into non-obese diabetic-severe combined immunodeficiency gamma mice brains, Sca1(+) pituitary tumor cells exhibited higher rates of tumor formation (brain tumors observed in 11/11 (100%) vs 7/12 (54%) of mice transplanted with Sca1(+) and Sca1(-) cells respectively). Magnetic resonance imaging and histological analysis of brain tumors showed that tumors derived from Sca1(+) pituitary tumor cells were also larger and plurihormonal. Our findings show that Sca1(+) cells derived from benign pituitary tumors exhibit an undifferentiated expression profile and tumor-proliferative advantages, and we propose that they could represent putative pituitary tumor stem/progenitor cells.

Update on subclinical hyperthyroidism.

Subclinical hyperthyroidism is defined by low or undetectable serum thyroid-stimulating hormone levels, with normal free thyroxine and total or free triiodothyronine levels. It can be caused by increased endogenous production of thyroid hormone (as in Graves disease or toxic nodular goiter), administration of thyroid hormone for treatment of malignant thyroid disease, or unintentional excessive thyroid hormone therapy. The rate of progression to overt hyperthyroidism is higher in persons who have suppressed thyroid-stimulating hormone levels compared with those who have low but detectable levels. Subclinical hyperthyroidism is associated with an increased risk of atrial fibrillation in older adults, and with decreased bone mineral density in postmenopausal women; however, the effectiveness of treatment in preventing these conditions is unknown. There is lesser-quality evidence suggesting an association between subclinical hyperthyroidism and other cardiovascular effects, including increased heart rate and left ventricular mass, and increased bone turnover markers. Possible associations between subclinical hyperthyroidism and quality of life parameters, cognition, and increased mortality rates are controversial. Prospective randomized controlled trials are needed to address the effects of early treatment on potential morbidities to help determine whether screening should be recommended in the asymptomatic general population.

Rat prolactinoma cell growth regulation by epidermal growth factor receptor ligands.

Epidermal growth factor (EGF) regulates pituitary development, hormone synthesis, and cell proliferation. Although ErbB receptor family members are expressed in pituitary tumors, the effects of EGF signaling on pituitary tumors are not known. Immunoprecipitation and Western blot confirmed EGF receptor (EGFR) and p185(c-neu) protein expression in GH3 lacto-somatotroph but not in adrenocorticotropic hormone-secreting AtT20 pituitary tumor cells. EGF (5 nmol/L) selectively enhanced baseline ( approximately 4-fold) and serum-induced (>6-fold) prolactin (PRL) mRNA levels, whereas gefitinib, an EGFR antagonist, suppressed serum-induced cell proliferation and Pttg1 expression, blocked PRL gene expression, and reversed EGF-mediated somatotroph-lactotroph phenotype switching. Downstream EGFR signaling by ERK, but not phosphoinositide-3-kinase or protein kinase C, mediated the gefitinib response. Tumors in athymic mice implanted s.c. with GH3 cells resulted in weight gain accompanied by increased serum PRL, growth hormone, and insulin growth factor 1. Gefitinib decreased tumor volumes and peripheral hormone levels by approximately 30% and restored normal mouse body weight patterns. Mice treated with gefitinib exhibited decreased tumor tissue ERK1/2 phosphorylation and down-regulated tumor PRL and Pttg1 mRNA abundance. These results show that EGFR inhibition controls tumor growth and PRL secretion in experimental lacto-somatotroph tumors. EGFR inhibitors could therefore be useful for the control of PRL secretion and tumor load in prolactinomas resistant to dopaminergic treatment, or for those prolactinomas undergoing rare malignant transformation.

Oct-1 induces pituitary tumor transforming gene expression in endocrine tumors.

As human pituitary tumor transforming gene (hPTTG1) is upregulated in endocrine tumors, we studied regulatory mechanisms for hPTTG1 expression. We identified Oct-1-binding motifs in the hPTTG1 promoter region and show Oct-1-specific binding to the hPTTG1 promoter using chromatin immunoprecipitation. We overexpressed Oct-1 and observed approximately 2.5-fold activation of hPTTG1 promoter luciferase constructs (-2642/-1 and -1717/-1). Transcriptional activation was abrogated by co-transfection of an inactive Oct-1 form lacking the POU domain or by utilizing mutated hPTTG1 promoters or mutants devoid of two Oct-1-binding motifs (-1717/-1mut, -637/-1 or -433/-1). Using biotin-streptavidin pull-down assays, we confirmed Oct-1 binding to the two octamer motifs in the hPTTG1 promoter (-1669/-1631 and -1401/-1361). Endogenous hPTTG1 mRNA and protein increased up to approximately fourfold in Oct-1 transfectants, as measured by real-time PCR and western blot. In contrast, siRNA-mediated suppression of endogenous Oct-1 attenuated both the hPTTG1 mRNA and protein levels. Using confocal immunofluorescence imaging, Oct-1 and hPTTG1 were concordantly upregulated in pituitary (57 and 62%, n=79, P<0.01) and breast tumor specimens (57 and 42%, n=77, P<0.05) respectively. The results show that Oct-1 transactivates hPTTG1, and both proteins are concordantly overexpressed in endocrine tumors, thus offering a mechanism for endocrine tumor hPTTG1 abundance.

Implication of pituitary tropic status on tumor development.

Pituitary tumor initiation and progression are associated with a plethora of genetic imbalances. Several genetic abnormalities have been described in pituitary tumors, from mutations in intracellular signaling (constitutive activation adenylyl cyclase) and growth factor pathways (epidermal growth factor receptor [EGFR]) to imbalance in cell cycle regulators (p16, p27, pRb). Unfortunately, most of these observations do not provide validated predictors of clinical behavior or of recurrence. The pituitary gland is notably plastic, and intrinsic and extrinsic stimuli result in profound growth changes ranging from hypoplasia to hyperplasia. The impact of pituitary tropic status on influencing neoplastic potential is difficult to test in human samples because the gland is not readily accessible for ongoing morphological observation. Animal models represent a functional approach to testing this hypothesis, and transgenic mouse models of pituitary tumor transforming gene (PTTG) inactivation or overexpression support the notion that pituitary tropic status directly correlates with likelihood for pituitary tumor formation. Understanding the mechanisms underlying changes in pituitary plasticity and their relationship to tumor development may contribute to the ability of regulating the development and progression of pituitary tumors.

Pituitary tumor transforming gene overexpression facilitates pituitary tumor development.

Intrinsic and extrinsic stimuli result in profound pituitary growth changes ranging from hypoplasia to hyperplasia. Pituitary tumor transforming gene (PTTG) abundance correlates with pituitary trophic status. Mice with Pttg inactivation exhibit pituitary hypoplasia, whereas targeted pituitary PTTG overexpression driven by alpha-subunit glycoprotein (alphaGSU) promoter results in focal pituitary hyperplasia. To test the impact of pituitary hyperplasia on tumor development, we crossbred alphaGSU.PTTG with Rb+/- mice, which develop pituitary tumors with high penetrance. Pituitary glands of resulting bitransgenic alphaGSU.PTTGxRb+/- mice were compared with monotransgenic alphaGSU.PTTG, Rb+/-, and wild-type mice. Confocal microscopy showed that PTTG-overexpressing cells have enlarged nuclei and marked redistribution of chromatin, and electron microscopy of alphaGSU.PTTG pituitaries showed enlarged gonadotrophs with prominent Golgi complexes and numerous secretory granules. These morphological findings were even more remarkable in alphaGSU.PTTGxRb+/- pituitaries. Mice from all four genotypes were sequentially imaged by magnetic resonance imaging to evaluate pituitary volume, and glands from alphaGSU.PTTGxRb+/- mice were the largest as early as 2 months of age (P = 0.0003). Cumulative incidence of pituitary tumors visualized by magnetic resonance imaging did not differ between Rb+/- and alphaGSU.PTTGxRb+/- mice. However, anterior lobe tumors determined after necropsy were 3.5 times more frequent in alphaGSU.PTTGxRb+/- than in Rb+/- mice (P = 0.0036), whereas the frequency of intermediate lobe tumors was similar. In summary, alphaGSU.PTTGxRb+/- pituitary glands exhibit enhanced cellular activity, increased volume, and higher prevalence of anterior pituitary tumors, indicating that changes in pituitary PTTG content directly relate to both pituitary trophic status and tumorigenic potential.

Treatment of acromegaly: future.

Recent progress in the therapy of GH-secreting pituitary tumors includes three treatment modalities: surgery, radiotherapy, and medications. A combination of treatment options is often required to attain therapeutic goals, increasing the potential for a combination of unwanted side effects. The focus of this review is to discuss medical therapy of GH-secreting adenomas focusing on newer drug compounds. In selected cases, therapeutic goals are attained with somatostatin analog treatment alone. The GH receptor antagonist controls IGF-I hypersecretion, and its use in combination with somatostatin analogs in selected patients is tempting but requires further evaluation. Somatostatin multireceptor ligand SOM230 and a somatostatin-dopamine chimeric ligand are new compounds that may improve therapy outcome. Careful individualization of therapy is important in deciding the ideal treatment approach, and primary medical therapy may be recommended in selected patients.

Expression of retinoblastoma protein in human growth hormone-secreting pituitary adenomas.

The retinoblastoma gene (RB1) is a tumor-suppressor gene in chromosomal region 13q14.2. Its role in the pathogenesis of pituitary tumors has not been fully clarified. Some studies have shown that losses in this chromosomal region are related to aggressive tumor behavior, although the retinoblastoma protein (pRB) is still expressed. Conversely, lack of expression of pRB was observed in one fourth of GH-secreting pituitary adenomas (GH-tumors). In order to further study the expression of pRB in GH-tumors, we evaluated this protein in 49 tumors from patients with acromegaly (20 noninvasive, 25 invasive, and 4 with no information) and 8 normal pituitaries using immunohistochemistry (IHC). Nuclear staining for pRB ranged from 0 to 90% (median 40%) in the tumors and from 40 to 80% (median 58%) in normal pituitaries. In 10 tumors (20% of total) the adenomatous cells were negative (5 cases) or had very low labeling (5 cases) for pRB. Sixty three percent (31/49) of the tumors showed staining in 10-80% of the cells and in 16% (8/49) of the cases >80% of the adenomatous cells were positive for pRB. The expression of pRB was not different in invasive and noninvasive tumors. In conclusion, pRB is underexpressed in a subgroup of GH-tumors, and this may represent an early event in the pathogenesis of this tumor subtype.

Teste agudo com octreotide subcutâneo como preditor de resposta ao tratamento com octreotide LAR® / Acute test with subcutaneous octreotide as a predictor of the response to treatment with octreotide LAR®

Os análogos da somatostatina são muito utilizados no tratamento da acromegalia. Com o objetivo de determinar o valor do teste agudo (TA) com octreotide subcutâneo (SC) como preditor da resposta ao tratamento com octreotide LAR®, analisamos os dados de 20 pacientes. Para o TA, amostras de sangue foram colhidas antes e duas horas após a administração de octreotide SC para a dosagem de GH. Os níveis de GH antes e após o TA foram 21,9 (2,3-143,4) e 3,1ng/mL (0,3-61,3), respectivamente. Foi considerado controle de doença: GH< 2,5ng/mL e IGF-I normal em algum momento durante o tratamento. A sensibilidade, especificidade e os valores preditivos positivo e negativo do TA foram 0,9, 0,6, 0,69 e 0,86 para redução de 75 por cento do GH no teste. Concluímos que, em nossa casuística, um decréscimo de 75 por cento dos níveis de GH no TA teve um bom poder discriminatório entre pacientes com maior e menor chance de resposta ao tratamento.

[Acute test with subcutaneous octreotide as a predictor of the response to treatment with octreotide LAR]. / Teste agudo com octreotide subcutâneo como preditor de resposta ao tratamento com octreotide LAR.

Somatostatin analogues are frequently used to treat acromegaly. To determine the value of the acute test (AT) with subcutaneous (SC) octreotide as a predictor of the response to treatment with octreotide LAR, we analyzed data from 20 patients. For the AT, blood was drawn before and two hours after the SC administration of octreotide for measuring GH. GH levels before and after the AT were 21.9 ng/mL (2.3-143.4) and 3.1 ng/mL (0.3-61.3), respectively. Control of the disease was defined as: GH< 2.5 ng/mL and normal IGF-I anytime during treatment. Sensitivity, specificity, positive and negative predictive values of the AT were 0.9, 0.6, 0.69 and 0.86 for a reduction of 75% of the GH on the test. From our sample we conclude that a 75% reduction of the GH levels during the acute test was able to discriminate patients with a higher or lower chance of responding to treatment.

Tumor deletion mapping of chromosomal region 13q14 in 43 growth hormone secreting pituitary adenomas.

Previous studies have reported allelic loss in chromosomal region 13q14 in pituitary tumors. However, the role of RB1 in this region has not been clarified. We performed a tumor deletion map of chromosomal region 13q14 with pituitary adenomas and matched blood samples of 43 patients with acromegaly. Twenty-one patients had non-invasive tumors, 19 had invasive tumors, and in 3 this information was not available. Results showed loss of heterozygosity in at least one microsatelite marker of region 13q14 in 12% (5 of 43) of the somatotropinomas. Retention of marker D13S1325, telomeric to RB1, suggests that the putative tumor suppressor gene is located centromeric to this region, which includes RB1 locus. The participation of RB1 was excluded in four of the five cases because retinoblastoma protein was shown to be positive in these tumors in our previous study. Allelic loss occurred in similar frequency in invasive and noninvasive adenomas. In summary, we confirmed the participation of chromosomal region 13q14 in a subset of GH-secreting adenomas with no regard to tumor grade. RB1 was not implicated, suggesting the participation of another tumor suppressor gene in this region during the first steps of somatotropinoma development.

Bases moleculares dos adenomas hipofisários com ênfase nos somatotropinomas / Molecular basis of pituitary adenomas with emphasis on somatotropinomas

Esta revisão descreve as bases moleculares dos adenomas hipofisários com ênfase nos tumores secretores de GH (somatotropinomas). São discutidos os papéis de genes de supressão tumoral (como RB1, MEN-1) e de oncogenes (como gsp, PTTG) na iniciação e progressão destes tumores. A caracterização destes marcadores moleculares pode ajudar na compreensão do comportamento tumoral, auxiliando a conduta terapêutica. Entretanto, apesar dos recentes avanços, ainda não é totalmente conhecida a seqüência de alterações genéticas envolvidas na patogênese destes adenomas.

Dependency and analgesia related to treatment with subcutaneous octreotide in patients with growth hormone-secreting tumors.

OBJECTIVE: To describe three patients diagnosed with somatotropinomas in whom the analgesic effect of octreotide was observed, along with dependency to the drug. METHODS: These patients had pituitary macroadenomas treated with transphenoidal surgery and pituitary radiotherapy, and received high daily doses (>900 microg/day) of subcutaneous octreotide because of persistent high levels of growth hormone and insulin-like growth factor I (IGF-I). RESULTS: Headache occurred prior to drug administration in all three cases, with relief soon after. We also observed tolerance to octreotide's analgesic and anti-secretory actions (one patient), craving for the drug (two patients), withdrawal syndrome (one patient), and drug abuse (one patient). CONCLUSION: Dependency syndrome may occur when high doses of octreotide are used, sometimes leading to drug abuse. Tolerance to the growth hormone anti-secretory effect of the drug may encourage physicians to increase doses to levels at which drug dependency has been observed. Sustained release somatostatin analogs may represent a solution to this problem.