bluuebunny/crossref_metadata_2025 huggingface dataset:
Effect of Blood Collection Tubes on Total Triiodothyronine and Other Laboratory Assays
Authors: Bowen Raffick AR , Chan Yung , Cohen Joshua , Rehak Nadja N , Hortin Glen L , Csako Gyorgy , Remaley Alan T
Published: December 2004

Background: Increased total triiodothyronine (TT3) assay results in apparently euthyroid patients triggered an investigation of the effect of blood collection tubes on serum TT3 and other laboratory assays.

Methods: We examined potential assay interference for three types of tubes: plastic Greiner Bio-One™ Vacuette™; glass Becton Dickinson (BD) Vacutainer™; and plastic BD Vacutainer SST™ tubes. Serum samples from apparently healthy volunteers (age range, 30–60 years; 15 males and 34 females) were collected in different tube types and analyzed in 17 immunoassays (n = 49), 30 clinical chemistry tests (n = 20), and 33 immunology assays (n = 15). Tube effects were also examined by adding pooled serum to different tube types.

Results: TT3 values, when measured by the IMMULITE™ 2000 but not the AxSYM™ analyzer, were significantly higher (P <0.0001) for SST (2.81 nmol/L) than either glass (2.15 nmol/L) or Vacuette (2.24 nmol/L) tubes. The effect was large enough to substantially shift the distribution of patient values, increasing the percentage of values above the reference interval from 11.3% to 35.8%. The degree of interference from SST tubes on TT3 differed among various tube lots and could be attributed to a tube additive shared by other plastic tubes. Results from several other tests statistically differed among tube types, but differences were not considered to be clinically significant.

Conclusions: Assay interferences from blood collection tubes represent challenges to clinical laboratories because they are not detected by the usual quality-control or proficiency testing programs. Laboratories can, however, address this problem by monitoring distribution of patients’ results.
Genetic and epigenetic regulation of human breast cancer progression and metastasis
Authors: Welch D R , Wei L L
Published: December 2004

Breast cancer is the most common malignancy and a major cause of cancer-related deaths among women in the United States and Western Europe (American Cancer Society 1998, Wingo et al. 1998). Most women succumb to breast cancer if their tumors metastasize but cures are more likely if the cancers remain localized (Harris et al. 1992a,b,c, Walker et al. 1997). Thus, a greater understanding of the metastatic process in human breast cancer should translate into substantial improvements in therapeutic outcome for breast cancer patients. Towards that end, we will review and summarize the literature about, and begin to develop a working model for, the genetics of human breast cancer metastasis. There have been great strides in recent years with regard to our overall understanding of metastasis. Yet our apparently straightforward objective - to define cause-effect relationships for genes in breast cancer - was difficult because of four issues. First, many reports fail to distinguish between oncogenesis and progression or invasion and metastasis when reporting data. Secondly, there is a failure, by some, to recognize that breast cancer is not a single disease, but a collection of diseases. This is particularly apparent in the genetics literature. Thirdly, it is difficult to evaluate the relative importance of correlative data, particularly as it relates to mechanistic control of steps in the metastatic cascade. Fourthly, there is a tremendous noise-to-signal ratio for genetics of late-stage, metastatic breast cancers resulting from genotypic instability, phenotypic drift and tumor heterogeneity.

Acknowledgements

We are particularly indebted to Dr Bernard E Weissman from the University of North Carolina at Chapel Hill. Much of the published work described here was done in conjunction with his laboratory. We also appreciate the efforts of Andrea Manni, P G Satyaswaroop, Michael Verderame, and Steven Goldberg for critical reading and helpful comments and suggestions. We also appreciate the support of grants from the US Army Medical Research and Material Command (DAMD17-96-6152 to D R W); the National Foundation for Cancer
Research (to D R W and L L W); PHS grant CA62168 (to D R W), the Latham Fund (L L W) and the Jake Gittlen Memorial Golf Tournament (D R W).
Assessing apoptosis: a critical survey.
Authors: Hall P A
Published: December 2004

Much progress has been made in the understanding of the process of apoptosis and there is a burgeoning literature pointing to it being a key phenomenon in tissue homeostasis. Moreover it is clear that derangements of the apoptotic cascade and its regulation can occur in a variety of disease states including in cancer. Many methods exist for the demonstration of apoptosis but some are not quantifiable. Others, such as enumeration of apoptotic bodies or end-labelling techniques, lend themselves to quantification. However, poor methods of quantification are sometimes employed. In this review, the methodological problems that can affect the assessment of apoptosis are discussed and suggestions made for more rigorous approaches.
Clinical studies of p53 in treatment and benefit of breast cancer patients.
Authors: Bergh J
Published: December 2004

This article describes p53 as a prognostic and predictive factor, together with some information on how best to determine the p53 status. By December 1998, 13,000 articles on p53 were identified on Pub Med, the National Library of Medicine. Within one week a further 62 articles were recorded making it difficult to give the complete p53 story. This review article will focus on discussing p53 in relation to its predictive potential. So far, no firm conclusions can be made based on the articles studied. This may be, in part, because many studies have used less than optimal techniques for determination of the p53 status, together with the fact that the studies lacked power to detect a potential difference in outcome from specific therapy in relation to p53 status.
Prognostic variables of papillary and follicular thyroid carcinoma patients with lymph node metastases and without distant metastases.
Authors: Lin J D , Liou M J , Chao T C , Weng H F , Ho Y S
Published: December 2004

From 1977 through 1995, 1,013 thyroid carcinoma patients received treatment and were followed up at Chang Gung Medical Center in Taiwan. To evaluate the prognostic variables of papillary and follicular thyroid carcinomas with limited lymph node metastases, a retrospective review of these patients was performed. Of these patients, 910 had papillary or follicular thyroid carcinoma, and 119 patients were categorized as clinical stage 2 with limited neck lymph node metastases only at the time of diagnosis. The patients were categorized into two groups as no recurrence and local recurrence or distant metastasis at the end of 1997. After the operations, radioactive iodide (131I) treatments were performed in 114 patients and external radiotherapy for neck region or distant metastases in 18 patients. The median follow-up period of these patients was 5.4 years. Clinical variables were coded in our computer for statistical analysis. After the treatments, 93 patients remained disease-free; 10 were in stage 2; 5 in stage 3; and 11 aggravated to stage 4. Of the clinical variables, age, post-operative first 1311 uptake scans, and 1-month post-operative thyroglobulin levels revealed statistically significant differences between the group which improved and the group which did not. During the follow-up period, five patients died; three patients died of thyroid cancer and two died of intercurrent diseases. Patients with papillary thyroid carcinoma revealed a higher percentage of lymph node metastases. Although limited lymph node metastases did not influence survival rate, patients with poor prognostic factors need more aggressive treatment to avoid progression of the cancer.
Local estrogen biosynthesis in males and females.
Authors: Simpson E , Rubin G , Clyne C , Robertson K , O'Donnell L , Davis S , Jones M
Published: December 2004

It is now apparent that in men and in postmenopausal women, estrogens have important physiological and pathophysiological roles. However, importantly, these actions are at a local level, namely paracrine, autocrine, and even 'intracrine' rather than endocrine in the classical sense. Thus for example local estrogen biosynthesis in the bones of men plays a hitherto unsuspected role in the maintenance of bone mineralization and in epiphyseal fusion; and in the testes, estrogen is essential for male germ cell development. On the other hand, in postmenopausal women, the mesenchymal cells of the breast are the major source of estrogen responsible for breast cancer development. This realization points to the importance of circulating C19 precursors in the maintenance of adequate estrogen biosynthesis in extragonadal sites and suggests the possibility of new therapies to block estrogen synthesis in a tissue-specific fashion.
Aromatase within the breast.
Authors: Yue W , Santen R J , Wang J P , Hamilton C J , Demers L M
Published: December 2004

In situ aromatization and enhanced uptake of estradiol from plasma are two potential mechanisms for maintenance of high concentrations of estradiol found in breast tumors of postmenopausal patients. To test the relative importance of these two mechanisms, a nude mouse model was established by inoculating aromatase (A+) and/or sham (A-) transfected MCF-7 cells into ovariectomized mice. Postmenopausal hormonal status was simulated by providing estradiol Silastic implants which clamped plasma estradiol levels at 5-20 pg/ml. We demonstrated that in situ aromatization rather than the uptake mechanism is the key determinant of tumor estradiol levels and tumor growth rate under conditions reflecting the postmenopausal state. The importance of intratumoral aromatase was also suggested by the findings that long-term estrogen deprivation increases sensitivity to estradiol and enhances aromatase activity in MCF-7 cells. The results of our in vivo and in vitro studies suggest that complete blockade of in situ aromatization in the breast would provide added benefit to postmenopausal breast cancer patients, especially those who relapse from antiestrogen therapy.
Aromatase inhibitors and enzyme stability.
Authors: Harada N , Honda S I , Hatano O
Published: December 2004

The effects of two steroidal (4-hydroxyandrostenedione and atamestane) and three non-steroidal (fadrozole, vorozole, and pentrozole) aromatase inhibitors on the levels of aromatase mRNA and protein were examined in vitro and in vivo. Immunocytochemistry revealed increased quantities of immunoreactive aromatase in human choriocarcinoma-derived JEG-3 cells in response to pretreatment with the non-steroidal inhibitors. To elucidate this effect in detail, aromatase protein in JEG-3 cells after treatment with various inhibitors was quantified using an enzyme-linked immunosorbent assay (ELISA). A time-dependent increase in aromatase protein in the cells was observed with all the aromatase inhibitors except 4-hydroxyandrostenedione, whereas aromatase mRNA levels in the cells remained unchanged during the inhibitor treatment. The three non-steroidal agents caused an approximately fourfold increase in aromatase protein in the cells 24 h after the treatment, as compared with untreated controls. The increase in aromatase protein in the cells was not blocked by treatment with cycloheximide, an inhibitor of protein synthesis. The inhibitors also appeared to block the rapid degradation observed in JEG-3 cells after induction by forskolin. In vivo, daily injection of the inhibitors into adult female mice caused increases in levels of both aromatase mRNA and protein in the ovary. The increase in aromatase mRNA in this in vivo study could be explained by an increase in gonadotropin concentrations in response to decreased plasma concentrations of estrogens. In conclusion, we suggest that aromatase inhibitors increase aromatase protein through stabilization and reduced protein turnover.
Cross-resistance to different aromatase inhibitors in breast cancer treatment.
Authors: L√∏nning P E
Published: December 2004

Recent studies have documented the biochemical and clinical efficacy of novel aromatase inhibitors. These drugs belong to one of two classes: non-steroidal and steroidal drugs, known to be different with respect to enzyme binding site and their effect on the aromatase enzyme. Several studies have now confirmed a lack of complete cross-resistance to drugs of the two classes. While some of these observations may be explained by a more potent aromatase inhibition caused by some aormatase inhibitors compared to others, this is not always the case. Such observations therefore focus on the importance of alternative mechanism of action like a differential influence on the intratumour aromatase enzyme by the different drugs. Current and future studies should aim at exploring the mechanism of cross-resistance and evaluate optimal use of different aromatase inhibitors in sequence or probably, also in concert.
Use of aromatase inhibitors in precocious puberty.
Authors: Feuillan P , Merke D , Leschek E W , Cutler G B
Published: December 2004

During puberty, estrogen causes breast maturation and growth of the uterine lining in girls, and accelerates linear growth and bone maturation in both boys and girls. Decreasing the biosynthesis of estrogen can attenuate these processes. In 12 girls with the McCune-Albright syndrome (MAS), in which precocious puberty is due to production of estrogen from ovarian cysts, testolactone (40 mg/kg per day) decreased the volume of ovarian cysts, the frequency of menses, and the rates of growth and bone maturation, for periods of 1-4 years. In a 6-month pilot study of 12 children (eight boys; four girls) with congenital adrenal hyperplasia, testolactone, in combination with an antiandrogen (flutamide), a mineralocorticoid (fludrocortisone acetate, Florinef), and a reduced glucocorticoid dose, improved the control of growth and bone maturation compared with conventional therapy. In a 6-year study of 10 boys with familial male precocious puberty, testolactone, in combination with an antiandrogen (spironolactone), decreased rates of growth and bone maturation, and increased predicted adult height. All patients who developed evidence for gonadotropin-dependent puberty were also treated with a GnRH analog. Testolactone had no important adverse effects in any group of patients, although the need for a four-times-daily dosing schedule made compliance difficult for many families. We conclude that suppressing of estrogen with testolactone was effective therapy, and that more potent and specific inhibitors of aromatase could further improve the treatment of these disorders.
Factors regulating the growth of metastatic cancer in bone.
Authors: Boyce B F , Yoneda T , Guise T A
Published: December 2004

Metastatic tumor cells can interfere directly with the function of bone cells involved in normal bone remodeling or indirectly by influencing the behavior of hematopoietic, stromal and other cells in bone marrow that interact with bone cells. Recent studies of metastatic cancer have revealed that tumor cells interact closely with vascular endothelial cells, basement membrane and bone marrow stromal cells through cell surface proteins or by releasing factors which affect the function of these cells. Bidirectional interaction between marrow cells and tumor cells can give the latter a selective advantage for growth in bone which can lead to the destruction of or to increased production of bone matrix. Understanding of the mechanisms involved in tumor metastasis and growth in bone has increased in recent years, and in this review we shall describe current knowledge of these mechanisms and of the predilection of certain types of cancers to metastasize to bone, their growth in the bone microenvironment and interactions between them and bone cells. Because metastatic breast cancer has been studied more than any other, we shall focus on it as a representative example, although the general principles apply to other types of cancer and to myeloma.
Prospects for the treatment of endocrine-responsive tumours.
Authors: Green S , Furr B
Published: December 2004

Much has been achieved over the last 30 years to improve the treatment of hormone-dependent cancer of the breast, ovary and prostate. The development of the antioestrogen tamoxifen (Nolvadex) spear-headed a range of drugs that counter the growth-promoting action of the female and male sex steroid hormones. An important additional benefit of endocrine therapies has been their low toxicity compared with conventional cancer chemotherapy thereby providing effective treatment with few serious side-effects and a sustained quality of life. Although some currently available therapies improve patient disease-free survival and overall survival, particularly when given in an adjuvant setting, they are not cures. There is, therefore, a continued need to develop newer therapies that extend the effectiveness of those currently available. This is particularly important when tumours either fail to respond or develop resistance to endocrine therapy. In this review, we examine how our improved understanding of the factors that influence the progression of endocrine-related tumours is leading to the development of novel therapies to treat both hormone-dependent and -independent tumours.
Involvement of steroid hormone and growth factor cross-talk in endocrine response in breast cancer.
Authors: Nicholson R I , McClelland R A , Robertson J F , Gee J M
Published: December 2004

Multiple lines of evidence implicate steroid hormone and growth factor cross-talk as a modulator of endocrine response in breast cancer and that aberrations in growth factor signaling pathways are a common element in the endocrine resistant phenotype. Delineation of these relationships is thus an important diagnostic goal in cancer research, while the targeting of aberrant growth factor signaling holds the promise of improving therapeutic response rates.
Prolactin involvement in breast cancer.
Authors: Vonderhaar B K
Published: December 2004

Normal development and differentiation of the mammary gland are profoundly influenced by prolactin (PRL). In rodent mammary cancer PRL plays a well defined role, but its role, in human breast cancer has not been appreciated until recently. It is now clear that breast tissue, both normal and malignant, is a significant source of extrapituitary PRL. Thus an autocrine/paracrine role of PRL in human breast cancer may be invoked. Both PRL and PRL receptor mRNA are expressed in the vast majority of breast cancer biopsies independent of estrogen and progesterone receptor status. An autocrine/paracrine PRL acting in human breast cancer requires that this hormone's action be blocked at the cellular level, as opposed to suppressing the synthesis and secretion of pituitary PRL. Mutants of PRL or human growth hormone are being explored which act as selective PRL antagonists. In addition, tamoxifen has been shown to act locally at the target tissue by binding directly to the PRL receptor and thus inhibiting PRL's action. These strategies may have clinical relevance in treating PRL-responsive human breast cancer.
Multiple endocrine neoplasia type 1.
Authors: Pannett A A , Thakker R V
Published: December 2004

Combined clinical and laboratory investigations of multiple endocrine neoplasia type 1 (MEN1) have resulted in an increased understanding of this disorder which may be inherited as an autosomal dominant condition. Defining the features of each disease manifestation in MEN1 has improved patient management and treatment, and has also facilitated a screening protocol to be instituted. The application of the techniques of molecular biology has enabled the identification of the gene causing MEN1 and the detection of mutations in patients. The function of the protein encoded by the MEN1 gene has been shown to be in the regulation of JunD-mediated transcription but much still remains to be elucidated. However, these recent advances provide for the identification of mutant MEN1 gene carriers who are at a high risk of developing this disorder and thus require regular and biochemical screening to detect the development of endocrine tumours.
Neuroendocrine cells in tumour growth of the prostate.
Authors: Abrahamsson P A
Published: December 2004

The prognostic significance of neuroendocrine differentiation in prostatic malignancy is controversial, but the results of recent studies with markers such as chromogranin A and neurone-specific enolase suggest that neuroendocrine differentiation, as reflected by increased tissue expression or blood concentrations of these neuroendocrine secretory products, is associated with a poor prognosis, tumour progression, and androgen independence. As all malignant neuroendocrine cells are devoid of androgen receptors and the expression of neuroendocrine cells is not suppressed by androgen ablation, clonal propagation of androgen receptor-negative neuroendocrine cells may have an important role in the development of androgen-independent prostatic carcinoma. This has significant implications for the treatment of prostate cancer, because several of the hormones that are secreted by neuroendocrine differentiated, malignant prostatic cells are potential candidates for use in drug treatment. A limited number of hormones have been tested in this context, in particular somatostatin, bombesin, and serotonin. As there is currently no successful treatment for differentiated prostate cancer, new therapeutic procedures and trials need to be developed to test drugs based on neuroendocrine hormones or their antagonists.
Editorial.
Authors: Lippman M
Published: December 2004

As we begin the new millennium, it is a great privilege for me to assume the responsibility of Editor-in-Chief of Endocrine-Related Cancer. As members of the Society for Endocrinology will know, Endocrine-Related Cancer< represents the further development and expansion of Reviews on Endocrine-Related Cancer which was acquired by the Society in 1993. Under the brilliant stewardship of its founding editor, Vivian James, Endocrine-Related Cancer has grown to be an outstanding journal publishing significant reviews in the area of intersection between endocrinology and cancer as well as proceedings of important scientific meetings and symposia around the world.
Hormone replacement therapy and breast cancer.
Authors: Jacobs H S
Published: December 2004

The concern that postmenopausal hormone replacement therapy (HRT) may cause cancer of the breast has lead to an enormous volume of research in epidemiology, endocrinology and tumour cell biology. The epidemiology has become extremely sophisticated because the anticipated effect is small and there are several confounding factors. The consensus today is that long-term HRT (>10 years) is associated with an increase in the risk of breast cancer which, on average, is equivalent to delaying menopause for the same period of time that the patient is on treatment. The risk is related to endogenous and exogenous oestrogen levels. Studies that have investigated individual susceptibility are reviewed, as are environmental factors such as the interaction of HRT with alcohol intake. The clinical implication of these data is that the dosage of HRT should be the smallest that is efficacious. Subcutaneous implants of oestrogen typically cause very high oestrogen levels and, in the opinion of this reviewer, should be restricted to women unable to take or absorb oestrogen by mouth or percutaneously. Finally, the issue of HRT for women with a history of breast cancer is considered. The potential is discussed for treatment of women with severe symptoms of oestrogen deficiency with a low dose of oestrogen, together with a selective oestrogen receptor modulator to protect the breast.
Hormone therapy in epithelial ovarian cancer.
Authors: Makar A P
Published: December 2004

Although epidemiologic studies, animal experiments and receptor studies have shown that not only normal ovaries but also many malignant ovarian tumors can be considered as endocrine related and hormone dependent, the place of hormonal therapy in the management of patients with ovarian cancer remains unsettled. Most trials of hormonal treatment in ovarian cancer have been retrospective, involved only limited numbers of patients, and lacked important patient-related data and information pertaining to tumor characteristics. In addition, a variety of hormonal preparations with different degrees of potency and in different dosages were included in these studies. A literature review shows that response to hormonal therapy even in a preterminal setting, is modest, with about 8% objective response but almost no side effects. In a similar patient setting, more toxic therapeutic agents do not yield a better response. The place of hormonal therapy in the management of patients with epithelial ovarian cancer needs more thorough evaluation in well-designed randomized trials.
Fibroblast growth factors, their receptors and signaling.
Authors: Powers C J , McLeskey S W , Wellstein A
Published: December 2004

Fibroblast growth factors (FGFs) are small polypeptide growth factors, all of whom share in common certain structural characteristics, and most of whom bind heparin avidly. Many FGFs contain signal peptides for secretion and are secreted into the extracellular environment, where they can bind to the heparan-like glycosaminoglycans (HLGAGs) of the extracellular matrix (ECM). From this reservoir, FGFs may act directly on target cells, or they can be released through digestion of the ECM or the activity of a carrier protein, a secreted FGF binding protein. FGFs bind specific receptor tyrosine kinases in the context of HLGAGs and this binding induces receptor dimerization and activation, ultimately resulting in the activation of various signal transduction cascades. Some FGFs are potent angiogenic factors and most play important roles in embryonic development and wound healing. FGF signaling also appears to play a role in tumor growth and angiogenesis, and autocrine FGF signaling may be particularly important in the progression of steroid hormone-dependent cancers to a hormone-independent state.
The epidermal growth factor receptor family as a central element for cellular signal transduction and diversification.
Authors: Prenzel N , Fischer O M , Streit S , Hart S , Ullrich A
Published: December 2004

Homeostasis of multicellular organisms is critically dependent on the correct interpretation of the plethora of signals which cells are exposed to during their lifespan. Various soluble factors regulate the activation state of cellular receptors which are coupled to a complex signal transduction network that ultimately generates signals defining the required biological response. The epidermal growth factor receptor (EGFR) family of receptor tyrosine kinases represents both key regulators of normal cellular development as well as critical players in a variety of pathophysiological phenomena. The aim of this review is to give a broad overview of signal transduction networks that are controlled by the EGFR superfamily of receptors in health and disease and its application for target-selective therapeutic intervention. Since the EGFR and HER2 were recently identified as critical players in the transduction of signals by a variety of cell surface receptors, such as G-protein-coupled receptors and integrins, our special focus is the mechanisms and significance of the interconnectivity between heterologous signalling systems.
The management of ductal carcinoma in situ of the breast.
Authors: Skinner K A , Silverstein M J
Published: December 2004

Ductal carcinoma in situ (DCIS) of the breast is a heterogeneous group of lesions with diverse malignant potential. It is the most rapidly growing subgroup within the breast cancer family with more than 42 000 new cases diagnosed in the United States during 2000. Most new cases are nonpalpable and are discovered mammographically. Treatment is controversial and ranges from excision only, to excision with radiation therapy, to mastectomy. Prospective randomized trials reveal an approximate 50% reduction in local recurrence rate overall with the addition of radiation therapy to excisional surgery, but the published prospective data do not allow the selection of subgroups in whom the benefit from radiation therapy is so small that its risks outweigh its benefits. Nonrandomized single facility series suggest that age, family history, nuclear grade, comedo-type necrosis, tumor size and margin width are all important factors in predicting local recurrence and that one or more of these factors could be used to select subgroups of patients who do not benefit sufficiently from radiation therapy to merit its use. When all patients with ductal carcinoma in situ are considered, the overall mortality from breast cancer is extremely low, only about 1-2%. When conservative treatment fails, approximately 50% of all local recurrences are invasive breast cancer. In spite of this, the mortality rate following invasive local recurrence is relatively low, about 12% with eight years of actuarial follow-up. Genetic changes routinely precede morphological evidence of malignant transformation. Lessons learned from ongoing basic science research will help us to identify those DCIS lesions that are unlikely to progress and to prevent progression in the rest.
Localization of parathyroid tumours in the minimally invasive era: which technique should be chosen? Population-based analysis of 253 patients undergoing parathyroidectomy and factors affecting parathyroid gland detection.
Authors: Lumachi F , Ermani M , Basso S , Zucchetta P , Borsato N , Favia G
Published: December 2004

A series of 253 consecutive patients with proved primary hyperparathyroidism due to parathyroid tumours was reviewed. There were 68 (26.9%) men and 185 (73.1%) women, with a median age of 57 years (range 13-82 years). All patients, prior to successful parathyroidectomy, underwent one or more preoperative localization procedures such as: neck ultrasonography (US) in 191 (75.5%), (201)Tl/(99m)Tc-pertechnetate subtraction scintigraphy (TPS) in 144 (56.9%), CT scan in 92 (36.4%), (99m)Tc-sestamibi/(99m)Tc-pertechnetate subtraction scintigraphy (MPS) in 90 (35.6%), selective venous sampling (SVS) with parathyroid hormone (PTH) assay in 30 (11.9%), and magnetic resonance imaging (MRI) in 6 (2.4%) patients. The results were compared with operative and histological findings that showed 235 (92.9%) solitary parathyroid adenomas, 13 (5.1%) carcinomas and 5 (2.0%) double adenomas. Sensitivity and positive predictive value were 82.9% and 93.8% for US, 83.6% and 91.8% for TPS, 81.3% and 98.7% for CT scan, 85.1% and 96.1% for MPS, 65.4% and 80.9% for SVS, and 80.0% and 80.0% for MRI respectively. No different results (P=NS) were found using US, TPS, MPS or CT scan, whereas SVS and MRI sensitivity was lower (P<0.05). The combination of MPS and US was 94.0% sensitive (P<0.05) but when TPS, CT scan or MRI were also used overall sensitivity did not improve significantly (P=NS). In conclusion, MPS should be used as the starting preoperative localization procedure, while US and MPS together represent the most reliable noninvasive localization tool. If MPS and US are negative or not in agreement, further studies are not cost-effective and the patient should undergo bilateral neck exploration.
Cyclooxygenase-2: a target for the prevention and treatment of breast cancer.
Authors: Howe L R , Subbaramaiah K , Brown A M , Dannenberg A J
Published: December 2004

Cyclooxygenase-2 (COX-2), an inducible prostaglandin synthase, is normally expressed in parts of the kidney and brain. Aberrant COX-2 expression was first reported in colorectal carcinomas and adenomas, and has now been detected in various human cancers, including those of the breast. Strikingly, COX-2 overexpression in murine mammary gland is sufficient to cause tumour formation. To date, the role of COX-2 in tumorigenesis has been most intensively studied in the colon. Thus, the relationship between COX-2 and neoplasia can best be illustrated with reference to intestinal tumorigenesis. Here we consider the potential utility of selective COX-2 inhibitors for the prevention and treatment of breast cancer. Data for cancers of the colon and breast are compared where possible. In addition, the mechanisms by which COX-2 is upregulated in cancers and contributes to tumorigenesis are discussed. Importantly, several recent studies of mammary tumorigenesis in animal models have found selective COX-2 inhibitors to be effective in the prevention and treatment of breast cancer. Clinical trials will be needed to determine whether COX-2 inhibition represents a useful approach to preventing or treating human breast cancer.
DNA methylation in breast cancer.
Authors: Yang X , Yan L , Davidson N E
Published: December 2004

Like all cancers, breast cancer is considered to result in part from the accumulation of multiple genetic alterations leading to oncogene overexpression and tumor suppressor loss. More recently, the role of epigenetic change as a distinct and crucial mechanism to silence a variety of methylated tissue-specific and imprinted genes has emerged in many cancer types. This review will briefly discuss basic aspects of DNA methylation, recent advances in DNA methyltransferases, the role of altered chromatin organization and the concept of gene transcriptional regulation built on methylated CpGs. In particular, we discuss epigenetic regulation of certain critical tumor suppressor and growth regulatory genes implicated in breast cancer, and its relevance to breast cancer diagnosis, prognosis, progression and therapy.
Treatment of medullary thyroid carcinoma: an update.
Authors: Orlandi F , Caraci P , Mussa A , Saggiorato E , Pancani G , Angeli A
Published: December 2004

Prognosis and treatment effectiveness of medullary thyroid carcinoma (MTC) are largely related to the tumour stage, so that early diagnosis represents an important goal for the management of patients. Recent advances in genetic testing have improved the clinical approach to the familial MTC syndromes. There is general agreement that the primary operation for MTC should obtain the complete removal of the neoplastic tissue in the neck, because any adjuvant treatment has never been proven to be effective. The management of residual/recurrent or metastatic MTC still remains controversial, although a multimodal approach to advanced disease may be of value in palliation or local control of tumour progression. The role of surgery, external radiotherapy, radionuclide therapy and medical treatment, including biological response modifiers and cytotoxic drugs, are reviewed and discussed.
Receptor tyrosine kinase signalling as a target for cancer intervention strategies.
Authors: Zwick E , Bange J , Ullrich A
Published: December 2004

In multicellular organisms, communication between individual cells is essential for the regulation and coordination of complex cellular processes such as growth, differentiation, migration and apoptosis. The plethora of signal transduction networks mediating these biological processes is regulated in part by polypeptide growth factors that can generate signals by activating cell surface receptors either in paracrine or autocrine manner. The primary mediators of such physiological cell responses are receptor tyrosine kinases (RTKs) that couple ligand binding to downstream signalling cascades and gene transcription. Investigations over the past 18 years have revealed that RTKs are not only key regulators of normal cellular processes but are also critically involved in the development and progression of human cancers. Therefore, signalling pathways controlled by tyrosine kinases offer unique opportunities for pharmaco logical intervention. The aim of this review is to give a broad overview of RTK signalling involved in tumorigenesis and the possibility of target-selective intervention for anti-cancer therapy.
Modulation of epidermal growth factor receptor in endocrine-resistant, oestrogen receptor-positive breast cancer.
Authors: Nicholson R I , Hutcheson I R , Harper M E , Knowlden J M , Barrow D , McClelland R A , Jones H E , Wakeling A E , Gee J M
Published: December 2004

There is an increasing body of evidence demonstrating that growth factor networks are highly interactive with oestrogen receptor (ER) signalling in the control of breast cancer growth. As such, tumour responses to anti- hormones are likely to be a composite of the ER and growth factor inhibitory activity of these agents. The current article examines the modulation of growth factor networks during endocrine response, and presents in vitro and clinical evidence that epidermal growth factor receptor signalling, maintained in either an ER-dependent or -independent manner, is critical to anti- hormonal-resistant breast cancer cell growth. The considerable potential of the epidermal growth factor receptor-selective tyrosine kinase inhibitor, ZD 1839 (Iressa; AstraZeneca) to efficiently treat, and perhaps even prevent, endocrine-resistant breast cancer is highlighted.
The IGF system and breast cancer.
Authors: Sachdev D , Yee D
Published: December 2004

The IGF system components have been implicated in breast cancer progression. IGF-I and IGF-II are mitogenic and anti-apoptotic peptides that influence the proliferation of various cell types including normal and transformed breast epithelial cells. The IGF system is a key growth regulatory pathway in breast cancer. As various components of the IGF system have been directly or indirectly implicated in breast cancer, it is essential to gain a better understanding of these in order to develop more specific therapeutic strategies for treating breast cancer.
Pituitary tumors: pathophysiology, clinical manifestations and management.
Authors: Arafah B M , Nasrallah M P
Published: December 2004

Pituitary tumors are frequently encountered intracranial neoplasms. They present with a variety of clinical manifestations that include symptoms and signs of excessive hormone secretion by the tumor, signs of hormone deficits by the normal pituitary gland and others related to expansion of the tumor mass and the resulting compression of surrounding structures such as the optic chiasm and cranial nerves. Advances in molecular biology, immunocytochemical staining and imaging, and the introduction of new treatment options have improved our understanding of the natural history of these adenomas and their management. Available treatments include surgical, medical and radiation therapy. Although the primary treatment for each tumor type may vary, it is important to consider all available options and select the most applicable for that patient. The interaction of all members of management team, including the primary care provider, the endocrinologist and the neurosurgeon in selecting the treatment course can only improve therapeutic outcome. Regardless of the initial choice of treatment,follow-up of all patients should be maintained indefinitely. The managing physician should be familiar with the natural history and long-term complications of pituitary adenomas, and with the side effects of treatments given over the years.
Mechanisms implicated in the growth regulatory effects of vitamin D in breast cancer.
Authors: Colston K W , Hansen C M√∏rk
Published: December 2004

It is now well established that, in addition to its central role in the maintenance of extracellular calcium levels and bone mineralization, 1,25-dihydroxyvitamin D(3) (1,25(OH)(2)D(3)), the active form of vitamin D, also acts as a modulator of cell growth and differentiation in a number of cell types, including breast cancer cells. The anti-proliferative effects of 1,25(OH)(2)D(3) have been linked to suppression of growth stimulatory signals and potentiation of growth inhibitory signals, which lead to changes in cell cycle regulators such as p21(WAF-1/CIP1) and p27(kip1), cyclins and retinoblastoma protein as well as induction of apoptosis. Such studies have led to interest in the potential use of 1,25(OH)(2)D(3) in the treatment or prevention of certain cancers. Since this approach is limited by the tendency of 1,25(OH)(2)D(3) to cause hypercalcaemia, synthetic vitamin D analogues have been developed which display separation of the growth regulating effects from calcium mobilizing actions. This review examines mechanisms by which 1,25(OH)(2)D(3) and its active analogues exert both anti-proliferative and pro-apoptotic effects and describes some of the synthetic analogues that have been shown to be of particular interest in relation to breast cancer.
Mechanisms involved in the progression of androgen-independent prostate cancers: it is not only the cancer cell's fault.
Authors: Arnold J T , Isaacs J T
Published: December 2004

The acquisition of an androgen-independent phenotype by prostate cancer cells is presently a death sentence for patients. In order to have a realistic chance of changing this outcome, an understanding of what drives the progression to androgen independence is critical. We review here a working hypothesis based on the position that the development of androgen-independent epithelial cells is the result of a series of cellular and molecular events within the whole tissue that culminates in the loss of normal tissue-maintained growth control. This tissue includes the epithelial and stromal cells, the supporting extracellular matrix and circulating hormones. This review discusses the characteristics of these malignant cells, the role of stromal cells involved in growth and the differentiation of epithelial cells, and the role of the extracellular matrix as a mediator of the phenotypes of stromal and epithelial cells. In addition, environmental, neuroendocrine and immune factors that may contribute to disturbance of the fine balance of the epithelial-stromal-extracellular matrix connection are considered. While the goal of many therapeutic approaches to prostate cancer has been androgen ablation or targeting the androgen receptor (AR) of epithelial cells, these therapies become ineffective as the cells progress beyond dependence on androgen for growth control. Twenty years ago Sir David Smithers debated that cancer is the result of loss of tolerance within tissues and the organizational failure of normal growth-control mechanisms. This is precipitated by prolonged or abnormal demands for regeneration or repair, rather than of any inherent disorder peculiar to each of the individual components involved. He wrote "It is not the cell itself that is disorderly, but its relationship with the rest of the tissue". We have gained significantly large amounts of precise data on the effects of androgenic ablation on cancerous prostate cells and on the role of the AR in prostate cancer. The need has come to compile this information towards a perspective of dysregulation of tissue as a whole, and to develop experimental systems to address this broader perspective to find and develop therapies for treatment and prevention.
The development and clinical use of trastuzumab (Herceptin).
Authors: Harries M , Smith I
Published: December 2004

HER-2 is a member of the c-erbB family of receptor tyrosine kinases and is overexpressed by 20-30% of human breast cancers. HER-2 overexpression is an independent adverse prognostic factor and may also predict for response to both chemotherapy and endocrine agents. Trastuzumab is a humanised monoclonal antibody that binds with high affinity to the extracellular domain of HER-2. In HER-2-overexpressing preclinical models trastuzumab has been shown to have a marked antiproliferative effect and demonstrates synergy with a number of cytotoxic drugs. Several phase II and phase III clinical trials have now been performed in patients with advanced breast cancer that overexpress HER-2. Trastuzumab was initially shown to be active and well tolerated as a single agent in heavily pretreated women. Subsequently, studies of first-line treatment for metastatic breast cancer have demonstrated an improvement in survival for trastuzumab when used in combination with either paclitaxel or an anthracycline-cyclophosphamide regimen compared with chemotherapy alone. Unexpectedly, the combination of trastuzumab and the anthracycline-containing regimen was associated with a significant incidence of cardiac dysfunction. The benefit of trastuzumab is generally confined to patients whose tumours have gene amplification as detected by fluorescence in situ hybridisation (FISH) and this is tightly associated with immunohistochemical (IHC) staining at the highest (3+) level. A small number of patients have IHC 2+ tumours together with FISH evidence of gene amplification and may also derive benefit from treatment. Trastuzumab has also been shown to be effective when used as first-line monotherapy for advanced breast cancer. Trials to date have employed trastuzumab in a weekly schedule, but there is emerging evidence that a three-weekly regimen may be as effective. Trastuzumab has shown encouraging activity when used with other agents including docetaxel and vinorelbine. The combination of trastuzumab, docetaxel, and platinum salts also appears to be very active. The role of trastuzumab as adjuvant therapy for early breast cancer is being tested in a number of large randomised trials.
Magnetic resonance imaging for primary breast cancer management: current role and new applications.
Authors: Esserman L , Wolverton D , Hylton N
Published: December 2004

Techniques for magnetic resonance (MR) imaging of the breast have been evolving over the past decade. The opportunities for integration of MR imaging into clinical breast cancer management and clinical research are increasing. In this paper, we will review the principles behind the creation of standard and MR images and use this as a platform to evaluate clinical studies and indications for the use and study of MR. In particular, we will focus on those areas where MR has the capability of changing care and/or improving our understanding of the biology of breast cancer. In addition, we will address areas where MR is not yet capable of adding value or where MR may lead to unnecessary procedures.
Interactions between radiotherapy and endocrine therapy in breast cancer.
Authors: del Moral R , L√≥pez M E , N√∫√±ez M I , Oliver F J , Valenzuela M T , Villalobos M , Ruiz de Almod√≥var J M
Published: December 2004

Whenever radiation therapy is given with curative intent there is the risk of serious damage to normal tissue. This risk increases with the dose of radiation, as does the probability of local tumour control. In the attempt to cure, the doses reach a level that inevitably causes some undesirable adverse effects, ranging from undetectable, or minimal, to unacceptably severe. Over the last few years, a number of reports have suggested that the prediction of normal tissue response after radiotherapy may be achieved by assays on samples withdrawn from the patients prior to treatment, although recent reports have described mixed results. The ability to predict tumour response to anti-hormones in patients with breast cancer has important implications with regard to treatment. Recent discoveries promise to provide individualized treatment options. However, there are no data to support that, used jointly, the combination of radiotherapy and hormone therapy may achieve an enhancement of breast cancer tumour response. Nowadays, development in cancer therapy is increasingly arising out of studies in basic science; its implementation in the hands of clinicians is improving the management of patients with cancer. In addition, as the biological aspects of irradiation and hormonal therapy offer an explanation, at least in part, for the outcome observed in patients with breast cancer after therapy, we have focused this review on trying to analyse the most relevant experimental research about the relative roles of radiotherapy and hormonal therapy, the corresponding side-effects and, taking into account recent advances, future areas of research that we consider of major importance in the field.