Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UMLS:C0178874 (tumor progression)
 40,807 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Twenty patients with recurrent or persistent epithelial ovarian cancer failing conventional therapies were treated with a single intraperitoneal injection of iodine-131-labeled OC 125 monoclonal antibody. Rare acute side effects were nausea and mild diarrhea. At doses up to 120 mCi of iodine-131, median white blood cell and platelet count nadirs were 3.6k/microliters and 187k/microliters, respectively. Two patients acquired thyroid toxicities despite thyroid blockage with "cold" iodine. One patient had transient TSH elevation while remaining clinically euthyroid, and 1 patient developed activation of a thyroid nodule and clinical hyperthyroidism. Dose-limiting toxicity has not yet been observed. Twelve of 20 patients are alive 3 to 17 months following therapy. Tumor progression was noted in the majority of patients, although 3 patients had documented decreases in tumor burden of short duration. We conclude that, at the doses examined, iodine-131 OC 125 can be safely administered intraperitoneally.
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PMID:Intraperitoneal radiolabeled OC 125 in patients with advanced ovarian cancer. 276 26

Epithelial properties of thyrocytes are difficult to maintain in conventional cell culture systems. We used bicameral chambers (Transwell) in attempts to establish a functional epithelium of thyrocytes of human origin. Thyroid follicle segments were isolated by collagenase digestion of paradenomatous tissue obtained at surgery for follicular adenoma and of tissue from glands with Graves' disease. After careful separation from connective tissue and single cells by centrifugation, the follicles were plated at high density on the collagen-coated filter of the chambers and cultured in Eagle's essential medium (EMEM) containing 10% fetal calf serum (FCS) or Coon's modified Hams medium enriched with five or six factors (5H, 6H); the latter media contained 5% FCS without (5H) or with (6H) thyrotropin (TSH). The follicles were converted into a confluent cell layer, which had similar DNA content irrespective of type of medium, after 4-6 days. Cells grown in EMEM or 5H established a transepithelial electrical resistance (R) of 200-500 omega.cm2 and was impermeable to [3H]inulin, indicating the formation of epithelial junctions. Addition of 6H to confluent cells initially cultured in EMEM or 5H caused a further increase of R, maximally to 1500 omega.cm2, along with a rise of the transepithelial potential difference; 6H promoted the monolayer formation of cells, increased the number of apical microvilli and reinforced the junctional distribution of actin, cadherin and ZO-1; 6H also enhanced the polarized secretion of [3H]leucine-labeled thyroglobulin into the apical medium. Cells from Graves' thyroid tissue established an epithelium on the filter with similar characteristics to that of normal thyrocytes; some platings contained in addition large numbers of HLA-DR positive cells with a dendritic shape. HLA-DR expression was generally absent in EMEM-or 5H-grown thyrocytes, but appeared in limited areas of the cell layer after 6H and was expressed by all epithelial cells after interferon-gamma stimulation for 48 h. We conclude that human thyrocytes form a tight and polarized epithelium when cultured on permeable filters. The polarized structure and function of the cells are positively regulated by TSH. The culture system may be useful in studies addressing the role of the epithelial phenotype (cell polarity and tight barrier) in normal thyroid function as well as in pathological processes in the thyroid, such as autoimmunity, cell transformation and tumor progression.
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PMID:Primary culture of human thyrocytes in Transwell bicameral chamber: thyrotropin promotes polarization and epithelial barrier function. 892 31

Thyroglobulin (Tg) measurement is primarily used to monitor patients with differentiated thyroid carcinoma (DTC) for tumor recurrence. Serum Tg levels principally integrate 3 variables: the mass of thyroid tissue present (benign or neoplastic); the degree of thyrotropin (TSH) receptor stimulation and tumor's intrinsic ability to synthesize and secrete Tg--a factor that needs to be assessed by a preoperative serum Tg determination. Serum Tg measurements should be interpreted relative to the TSH status of the patient. When TSH is low (on levothyroxine [LT4] therapy) basal serum Tg may be undetectable and recombinant human thyrotropin (rhTSH) administration may be needed to increase serum Tg into the measureable range. The Tg fold response to rhTSH (rhTSH-stimulated Tg/basal Tg) is an index of the tumor's sensitivity to TSH. Normal thyroid remnant and well-differentiated thyroid tumors display a greater (>10-fold) serum Tg response to TSH stimulation compared with less well-differentiated tumors (<3-fold). The factors influencing the response include the magnitude and chronicity of the serum TSH elevation, the mass of thyroid tissue and the TSH receptor status of the tumor. Technical problems still compromise the clinical utility of serum Tg measurement. Thyroglobulin autoantibodies are present in approximately 20% of all DTC patients and cause either underestimation or overestimation of serum Tg measurements made by immunometric assay (IMA) and radioimmunoassay (RIA) methods, respectively. Other technical problems include poor interassay precision, "hook" effects (IMA methods), intermethod standardization differences, and suboptimal sensitivity for detecting small amounts of tumor during TSH suppression. When TSH is suppressed, the basal serum Tg provides an integrated index of thyroid tissue mass and its capability to secrete Tg. Serial measurements of basal Tg concentrations can be used to monitor tumor progression or regression. The development of a low (<1 ng/mL) serum Tg (on LT4 therapy) by the second postoperative year signifies a low 5-year recurrence risk whereas a rising serum Tg in the face of TSH suppression is an abnormal response consistent with recurrence. The optimal degree of TSH suppression for a patient should be based on clinical judgment, relative to tumor staging and the risks from iatrogenic hyperthyroidism. Despite current technical limitations, serum Tg measurement is the cornerstone of long-term monitoring for most DTC patients. For optimal use of serum Tg, it is necessary to understand the pathophysiology of Tg secretion, the limitations of Tg methods and the use of rhTSH to overcome the insensitivity of current Tg methods.
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PMID:Detection of residual and recurrent differentiated thyroid carcinoma by serum thyroglobulin measurement. 1036 73

The recent cloning of the gene encoding the sodium/iodide symporter (NIS) has enabled better characterization of the molecular mechanisms underlying iodide transport, thus opening the way to clarifying its role in thyroid diseases. Several studies, at both the mRNA and the protein expression levels, have demonstrated that TSH, the primary regulator of iodide uptake, upregulates NIS gene expression and NIS protein abundance, both in vitro and in vivo. However, other factors, including iodide, retinoic acid, transforming growth factor-beta, interleukin-1alpha and tumour necrosis factor alpha, may participate in the regulation of NIS expression. Investigation of NIS mRNA expression in different thyroid tissues has revealed increased levels of expression in Graves' disease and toxic adenomas, whereas a reduction or loss of NIS transcript was detected in differentiated thyroid carcinomas, despite the expression of other specific thyroid markers. NIS mRNA was also detected in non-thyroid tissues able to concentrate radioiodine, including salivary glands, stomach, thymus and breast. The production of specific antibodies against the NIS has facilitated study of the expression of the symporter protein. Despite of the presence of high levels of human (h)NIS mRNA, normal thyroid glands exhibit a heterogeneous expression of NIS protein, limited to the basolateral membrane of the thyrocytes. By immunohistochemistry, staining of hNIS protein was stronger in Graves' and toxic adenomas and reduced in thyroid carcinomas. Measurement of iodide uptake by thyroid cancer cells is the cornerstone of the follow-up and treatment of patients with thyroid cancer. However, radioiodide uptake is found only in about 67% of patients with persistent or recurrent disease. Several studies have demonstrated a decrease in or a loss of NIS expression in primary human thyroid carcinomas, and immunohistochemical studies have confirmed this considerably decreased expression of the NIS protein in thyroid cancer tissues, suggesting that the low expression of NIS may represent an early abnormality in the pathway of thyroid cell transformation, rather than being a consequence of cancer progression. The relationship between radioiodine uptake and NIS expression by thyroid cancer cells require further study. New strategies, based on manipulation of NIS expression, to obtain NIS gene reactivation or for use as NIS gene therapy in the treatment of radiosensitive cancer, are also being investigated.
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PMID:Sodium/iodide symporter: a key transport system in thyroid cancer cell metabolism. 1057 59

Langerhans cell histiocytosis (LCH) is a rare disorder in which granulomatous deposits occur at multiple sites within the body, but which often involves the hypothalamo-pituitary axis (HPA). Although diabetes insipidus (DI) is a well recognized complication, the frequency of anterior pituitary and other nonendocrine hypothalamic (NEH) involvement has not been well defined, particularly in adult patients with the disease. We have evaluated the frequency and progression of LCH-related anterior pituitary and other NEH dysfunction and their responses to treatment in 12 adult patients with histologically proven LCH and DI. They were followed up for a median of 11.5 yr (range, 3-28 yr) after the diagnosis of DI was made. Study evaluations comprised clinical (including formal psychometric assessment where appropriate), basal and dynamic pituitary function tests, and radiology with computed tomography and/or magnetic resonance imaging scanning. Eleven patients received systemic treatment, and 5 patients received external beam radiotherapy confined to the HPA. The median age at diagnosis of DI was 34 yr (range, 2-47 yr); DI was the presenting symptom in four patients, whereas the remaining eight each developed DI 1-20 yr (median, 2 yr) after the diagnosis of LCH. Eight patients developed one or more anterior pituitary hormonal deficiencies at a median of 4.5 yr (range, 2-22 yr) after the diagnosis of DI: GH deficiency developed in eight patients (median, 2 yr; range, 2-22 yr), FSH-LH deficiency in 7 patients (median, 7 yr; range, 2-22 yr), and TSH and ACTH deficiency in five patients (median, 10 yr; range, 3-16 and 3-19 yr), respectively; five patients developed panhypopituitarism. In addition, seven patients with anterior pituitary dysfunction also developed symptoms of other NEH dysfunctions at a median of 10 yr (range, 1-23 yr): five morbid obesity (body mass index, >35), five short term memory deficits, four sleeping disorders, two disorders of thermoregulation, and one adipsia. All patients developed disease outside of the hypothalamus during the course of the study, and no fluctuation of disease activity in the HPA region was noted. Radiological examination of the HPA was abnormal in each of the eight patients with anterior pituitary involvement and in the seven patients with NEH dysfunction (one or more abnormalities): seven had thickening of the infundibulum, and one had hypothalamic and thalamic signal changes. All patients who had a magnetic resonance imaging scan had absence of the bright spot of the posterior pituitary on the T1-weighted sequences, and in four patients with DI and normal anterior pituitary function this was the only abnormality. The five patients who received radiotherapy to the HPA achieved a partial or complete radiological response, and there was no evidence of tumor progression in this region. No form of therapy, including chemotherapy, improved any established hormonal deficiencies or symptoms of NEH. In summary, in our adult patients with hypothalamic LCH and DI, anterior pituitary hormonal deficiencies developed in 8 of 12 patients; these occurred over the course of 20 yr. They were frequently accompanied by structural changes of the HPA, although these were often subtle in nature. In addition, symptoms of NEH dysfunction developed in up to 90% of such patients and complicated management. Radiotherapy may be useful in achieving local control of tumor, but established anterior, posterior pituitary, and other NEH dysfunctions do not improve in response to current treatment protocols. Patients with LCH and DI, particularly those with multisystem disease and a structural lesion on radiology, should undergo regular and prolonged endocrine assessment to establish anterior pituitary deficiency and provide appropriate hormonal replacement.
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PMID:Hypothalamo-pituitary abnormalities in adult patients with langerhans cell histiocytosis: clinical, endocrinological, and radiological features and response to treatment. 1077 Jan 68

Recombinant TSH is effective in providing exogenous TSH stimulation for patients with differentiated thyroid cancer on thyroid hormone-suppressive therapy. It allows for detection of thyroid remnant and metastases by radioiodine scan and by serum thyroglobulin determination. The sensitivity and image quality of the WBS are similar after rTSH and after THSH withdrawal in the majority of patients. The equivalent 100% sensitivity of rTSH- and withdrawal-stimulated serum thyroglobulin measurement alone in identifying patients with radioiodine uptake outside the thyroid bed [38] may eventually lead to more extensive use of serum thyroglobulin testing after rTSH, with more selective application of radioiodine WBS [39]. Currently, a phase IV trial is in progress to evaluate the efficacy of rTSH-stimulated thyroglobulin levels as the primary modality for long-term follow-up of low risk thyroid cancer patients. The use of rTSH prevents the morbidity, metabolic impairment and the risk of tumor progression associated with THST withdrawal, because of shorter exposure time to elevated TSH [38]. Furthermore, it decreases the radiation exposure of healthy tissues due to faster iodine clearance in euthyroidism. rTSH is well tolerated, with transient nausea in 10.5% and headache in 7.3% of patients. No antibodies specific to rTSH were documented, even after multiple courses of the drug. Currently, rTSH is suggested for patients who do not respond to hormone withdrawal or cannot tolerate hypothyroidism. For patients with low risk of tumor recurrence, rTSH-stimulated testing may be used at 6-12 months after postoperative I-131 ablation and with a repeat cycle of rTSH one year later, followed by testing every 3-5 years. In high risk patients, one set of negative I-131 scan and thyroglobulin test results after hormone withdrawal are recommended before using rTSH testing, because of a greater sensitivity of the withdrawal scan and because rTSH is not currently approved for subsequent I-131 therapy often indicated in these patients [24]. Subsequently, two cycles of rTSH testing are recommended at 6-12 month intervals, followed by testing every 1-3 years for at least the first decade after initial diagnosis. The cost of this commercially available form of rTSH has been considered a major impediment to its common use; however, this should be weighed against the loss of productivity of working hours related to withdrawal [40]. In the therapeutic setting, rTSH is the only acceptable option in a subgroup of patients with hypopituitarism, ischemic heart disease, a history of "myxedema madness," debilitation due to advanced disease, or inability to elicit TSH elevation due to continued production of thyroxine by thyroid remnant or metastatic tumor [33,38]. In conclusion, recombinant TSH facilitates the management of patients with differentiated thyroid carcinoma. It increases the sensitivity of thyroglobulin testing during thyroid hormone suppression therapy and enables radioiodine uptake for whole-body scan and occasionally for radioiodine therapy, without the need for prolonged THST withdrawal and its associated hypothyroidism, reduced quality of life and risk of tumor progression.
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PMID:Recombinant thyroid-stimulating hormone in differentiated thyroid cancer. 1172 83

One of the greatest challenges in the management of patients with follicular cell-derived thyroid cancer is the treatment of tumors that progress despite surgery, radioiodine, and T(4) suppression of TSH. As knowledge of thyroid cancer biology improves, the potential exists to develop compounds targeted to treat thyroid cancers that do not respond to traditional therapy. Recently, the development of therapies targeted against specific molecular pathways involved in cancer progression has resulted in dramatic responses in patients with chronic myelogenous leukemia, gastrointestinal stromal tumors, and other cancers. A number of compounds are currently being evaluated in clinical trials that alter pathways involved thyroid cancer, and several of these agents have been tested in thyroid cancer in vitro and in vivo. In this review we will discuss the mechanisms of action and preclinical/clinical data for several of these compounds that have the potential to play an important role in the management of thyroid cancer in the future.
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PMID:Clinical review 158: Beyond radioiodine: a review of potential new therapeutic approaches for thyroid cancer. 1272 38

Pituitary adenomas, almost invariably adenomas, account for 10% to 15% of all intracranial neoplasms and are incidentally detected in up to 27% of non selected autopsies. They are morphologically classified as microadenomas (diameter < 1 cm) or macroadenomas, which can be enclosed, invasive and/or expansive. Functionally, they are classified as secreting adenomas (PRL, GH, ACTH, TSH, LH, and FSH, and those co-secreting two or more hormones), and clinically non secreting or "non functioning" tumors. Diagnosis is based on the hypersecretion phenotype (acromegaly, Cushing, etc), and on mass effect of macroadenomas leading to neurological disturbances, mainly visual complaints and headache. Pituitary tumorigenesis mechanisms include those of primary hypothalamic versus pituitary origin, the latter is supported by evidence of pituitary adenoma monoclonality, as well as the absence of hyperplastic tissue surrounding the surgically removed tumor, and the relative independence of tumor hypothalamic control. Nevertheless, a permissive role of the hypothalamus on tumor progression is also postulated. Several molecular mechanisms involved in pituitary tumorigenesis have been unraveled including oncogenes, tumor suppressor genes and growth factors involved in neoplastic development, and will be described in this review.
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PMID:[Pituitary tumorigenesis]. 1644 45

NADPH oxidase 4 (NOX4) belongs to the NOX family that generates reactive oxygen species (ROS). Function and tissue distribution of NOX4 have not yet been entirely clarified. To date, in the thyroid gland, only DUOX1/2 NOX systems have been described. NOX4 mRNA expression, as shown by real-time PCR, was present in normal thyroid tissue, regulated by TSH and significantly increased in differentiated cancer tissues. TSH increased the protein level of NOX4 in human thyroid primary culture and NOX4-dependent ROS generation. NOX4 immunostaining was detected in normal and pathologic thyroid tissues. In normal thyroid tissue, staining was heterogeneous and mostly found in activated columnar thyrocytes but absent in quiescent flat cells. Papillary and follicular thyroid carcinomas displayed more homogeneous staining. The p22(phox) protein that forms a heterodimeric enzyme complex with NOX4 displayed an identical cellular expression pattern and was also positively regulated by TSH. ROS may have various biological effects, depending on the site of production. Intracellular NOX4-p22(phox) localization suggests a role in cytoplasmic redox signaling, in contrast to the DUOX localization at the apical membrane that corresponds to an extracellular H(2)O(2) production. Increased NOX4-p22(phox) in cancer might be related to a higher proliferation rate and tumor progression but a role in the development of tumors has to be further studied and established in the future.
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PMID:Intracellular expression of reactive oxygen species-generating NADPH oxidase NOX4 in normal and cancer thyroid tissues. 1977 36

Malignant tumours specific for the thyroid gland originate from either the follicular cells (papillary, follicular undifferentiated carcinomas) or the parafollicular C-cell system (medullary carcinomas). Regarding the follicle derived carcinomas, various types of data indicate that radiation exposure, for example therapeutic radiation given to children for benign disorders in the head and neck area, is an important risk factor. Dietary components may also be relevant. The marked female predominance. which is not specific for malignant tumours, is probably the result of hormonal cofactors and differences in growth promotion of early lesions (microcarcinomas). Further development of follicle derived tumours is characterized by decreasing tumour cell dependence of TSH, along with the introduction of autocrine loops, e.g. expression of the TGF alpha/EGF-receptor system. and such mechanisms may in part explain the development of autonomous growth. In parallel with these phenotypic changes, several alterations have also been described in various thyroid tumours, including the medullary carcinomas, for example in the ras and ret genes. Activation of some oncogenes, like the EGF-receptor system, may also be relevant for late tumor progression and hence of prognostic value. to-ether with other factors like p53 and nm23. In addition to classical clinocopathological features, molecular data are of increasing importance in biological grading of thyroid tumours.
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PMID:Thyroid-cancer - some aspects of epidemiology and etiologic factors, pathological features and tumor biology. 2156 3


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