Acetato de lanreotida e acetato de octreotida de liberação prolongada para o tratamento de pacientes com sintomas associados a tumores endócrinos gastroenteropancreáticos funcionais / Lanreotide acetate and extended-release octreotide acetate for the treatment of patients with symptoms associated with functional gastroenteropancreatic endocrine tumors

INTRODUÇÃO: Os tumores neuroendócrinos (TNE) são neoplasias, com origem mais comum no trato gastrointestinal, que podem cursar com liberação de hormônios associado a sintomas, levando a síndrome carcinoide, com incidência anual estimada em 0,25/1.000.000 na Europa (ano de 2008). As manifestações clínicas mais comuns incluem diarreia secretória e rubor súbito, mas a diarreia é considerada mais debilitante com potencial risco de morte. Quando o tratamento curativo com ressecção completa não é viável pela presença de doença metastática, o tratamento é direcionado para o controle dos sintomas da síndrome carcinoide e os análogos da somatostatina (octreotida ou lanreotida) são considerados terapia de primeira linha na SC. PERGUNTAS DE PESQUISA: O acetato de octreotida de liberação prolongada (octreotida LAR) e o acetato de lanreotida de liberação prolongada (lanreotida LP) são eficazes, seguros e custo-efetivos para o tratamento dos sintomas relacionados à SC associados ao TNE gastroenteropancreático funcional em pacientes adultos? EVIDÊNCIAS CLÍNICAS: Foram selecionados três ensaios clínico

Oncocrinology.

Oncocrinology is the science which studies the complex bi-directional relationship between cancer and the endocrine system, including pathophysiological links, clinical presentation and the impact of cancer treatment and endocrine therapy. This review describes the vast spectrum of the complex, multifacted relationship between the endocrine system and malignancy. It also includes the endocrine aspects of anti-cancer treatment, and the need for oncovigilance with endocrine therapy.

Adipose Tissue, Obesity and Adiponectin: Role in Endocrine Cancer Risk.

Adipose tissue has been recognized as a complex organ with endocrine and metabolic roles. The excess of fat mass, as occurs during overweight and obesity states, alters the regulation of adipose tissue, contributing to the development of obesity-related disorders. In this regard, many epidemiological studies shown an association between obesity and numerous types of malignancies, comprising those linked to the endocrine system (e.g., breast, endometrial, ovarian, thyroid and prostate cancers). Multiple factors may contribute to this phenomenon, such as hyperinsulinemia, dyslipidemia, oxidative stress, inflammation, abnormal adipokines secretion and metabolism. Among adipokines, growing interest has been placed in recent years on adiponectin (APN) and on its role in carcinogenesis. APN is secreted by adipose tissue and exerts both anti-inflammatory and anti-proliferative actions. It has been demonstrated that APN is drastically decreased in obese individuals and that it can play a crucial role in tumor growth. Although literature data on the impact of APN on carcinogenesis are sometimes conflicting, the most accredited hypothesis is that it has a protective action, preventing cancer development and progression. The aim of the present review is to summarize the currently available evidence on the involvement of APN and its signaling in the etiology of cancer, focusing on endocrine malignancies.

Systems biology: perspectives on multiscale modeling in research on endocrine-related cancers.

Drawing on concepts from experimental biology, computer science, informatics, mathematics and statistics, systems biologists integrate data across diverse platforms and scales of time and space to create computational and mathematical models of the integrative, holistic functions of living systems. Endocrine-related cancers are well suited to study from a systems perspective because of the signaling complexities arising from the roles of growth factors, hormones and their receptors as critical regulators of cancer cell biology and from the interactions among cancer cells, normal cells and signaling molecules in the tumor microenvironment. Moreover, growth factors, hormones and their receptors are often effective targets for therapeutic intervention, such as estrogen biosynthesis, estrogen receptors or HER2 in breast cancer and androgen receptors in prostate cancer. Given the complexity underlying the molecular control networks in these cancers, a simple, intuitive understanding of how endocrine-related cancers respond to therapeutic protocols has proved incomplete and unsatisfactory. Systems biology offers an alternative paradigm for understanding these cancers and their treatment. To correctly interpret the results of systems-based studies requires some knowledge of how in silico models are built, and how they are used to describe a system and to predict the effects of perturbations on system function. In this review, we provide a general perspective on the field of cancer systems biology, and we explore some of the advantages, limitations and pitfalls associated with using predictive multiscale modeling to study endocrine-related cancers.

Linking obesity-induced leptin-signaling pathways to common endocrine-related cancers in women.

Obesity is related to many major diseases and cancers. Women have higher rates of obesity and obesity is linked to commonly occurring cancers in women. However, there is a lack of knowledge of the unique mechanism(s) involved in each type of cancer. The objective of this review is to highlight the need for novel experimental approaches and a better understanding of the common and unique pathways to resolve controversies regarding the role of obesity in cancer. In women, there is a link between hormones and obesity-associated genes in cancer development. Leptin is an obesity-associated gene that has been studied extensively in cancers; however, whether the defect is in the leptin gene or in its signaling pathways remains unclear. Both leptin and its receptor have been positively correlated with cancer progression in some endocrine-related cancers in women. This review offers an up-to-date and cohesive review of both upstream and downstream pathways of leptin signaling in cancer and a comprehensive picture of cancer pathogenesis in light of current evidence of leptin effects in several major types of cancer. This work is intended to aid in the design of better therapeutic strategies for obese/overweight women with cancer.

Environmental epigenetics: a role in endocrine disease?

Endocrine disrupting chemicals that are structurally similar to steroid or amine hormones have the potential to mimic endocrine endpoints at the receptor level. However, more recently, epigenetic-induced alteration in gene expression has emerged as an alternative way in which environmental compounds may exert endocrine effects. We review concepts related to environmental epigenetics and relevance for endocrinology through three broad examples: 1) effect of early-life nutritional exposures on future obesity and insulin resistance, 2) effect of lifetime environmental exposures such as ionizing radiation on endocrine cancer risk, and 3) potential for compounds previously classified as endocrine disrupting to additionally or alternatively exert effects through epigenetic mechanisms. The field of environmental epigenetics is still nascent, and additional studies are needed to confirm and reinforce data derived from animal models and preliminary human studies. Current evidence suggests that environmental exposures may significantly impact expression of endocrine-related genes and thereby affect clinical endocrine outcomes.

Clinical outcomes in the management of congenital adrenal hyperplasia.

Congenital adrenal hyperplasia (CAH) is a group of disorders affecting adrenal steroid synthesis. The most common form, 21-hydroxylase deficiency, leads to decreased production of cortisol and aldosterone with increased androgen secretion. In classic CAH glucocorticoid treatment can be life-saving, and provides symptom control, but must be given in an unphysiological manner with the risk of negative long-term outcomes. A late diagnosis or a severe phenotype or genotype has also a negative impact. These factors can result in impaired quality of life (QoL), increased cardiometabolic risk, short stature, osteoporosis and fractures, benign tumors, decreased fertility, and vocal problems. The prognosis has improved during the last decades, thanks to better clinical management and nowadays the most affected patients seem to have a good QoL. Very few patients above the age of 60 years have, however, been studied. Classifying patients according to genotype may give additional useful clinical information. The introduction of neonatal CAH screening may enhance long-term results. Monitoring of different risk factors and negative consequences should be done regularly in an attempt to improve clinical outcomes further.

Diffuse endocrine system, neuroendocrine tumors and immunity: what's new?

During the last two decades, research into the modulation of immunity by the neuroendocrine system has flourished, unravelling significant effects of several neuropeptides, including somatostatin (SRIH), and especially cortistatin (CST), on immune cells. Scientists have learnt that the diffuse neuroendocrine system can regulate the immune system at all its levels: innate immunity, adaptive immunity, and maintenance of immune tolerance. Compelling studies with animal models have demonstrated that some neuropeptides may be effective in treating inflammatory disorders, such as sepsis, and T helper 1-driven autoimmune diseases, like Crohn's disease and rheumatoid arthritis. Here, the latest findings concerning the neuroendocrine control of the immune system are discussed, with emphasis on SRIH and CST. The second part of the review deals with the immune response to neuroendocrine tumors (NETs). The anti-NET immune response has been described in the last years and it is still being characterized, similarly to what is happening for several other types of cancer. In parallel with investigations addressing the mechanisms by which the immune system contrasts NET growth and spreading, ground-breaking clinical trials of dendritic cell vaccination as immunotherapy for metastatic NETs have shown in principle that the immune reaction to NETs can be exploited for treatment.

The role of telomeres and telomerase in endocrine tumors.

The enzyme, telomerase, is a reverse transcriptase that synthesizes the telomeric ends of linear chromosomes and compensate for the shortened telomere, thereby immortalizing the cell. It is present at the blastocyst stage of embryological development, low or undetectable in most somatic cells, and activated in cancer. Because of its strong association with cancer cell immortalization and proliferation, numerous attempts have been made to capitalize on its diagnostic, prognostic, and therapeutic potential. Herein we discuss the role of telomerase in normal, benign, and cancerous endocrine tissues.

MicroRNAs: a complex regulatory network drives the acquisition of malignant cell phenotype.

Several lines of evidence indicate that tumorigenesis is a complex multistep process, and that most, if not all, cancers acquire the same set of functional capabilities during development and progression, albeit through various mechanistic strategies. Increasing data show an important role of microRNAs (miRNAs or miRs) in regulating various aspects of cancer biology. This review describes the role of microRNAs during the multiple steps that drive the progressive transformation of normal cells into highly malignant derivatives, outlining the role of microRNAs in regulating the common hallmarks of tumorigenesis: self-sufficiency in growth signals, insensitivity to antigrowth signals, abnormal apoptosis, limitless replicative potential, induction and sustained angiogenesis, and tissue invasion and metastasis. Recent evidence suggests an important role of microRNAs in the regulation of the expression of most genes regulating and coordinating a wide variety of processes in endocrine glands. We will highlight microRNAs of potential relevance to endocrine tumors and hormone-dependent cancers. Through this overview of how microRNAs regulate multiple targets and entire pathways, we will provide insight into the potential to develop new molecular microRNA-targeted therapies for endocrine tumors.

[Is there any relationship between rural environmental factors and reproductive health in the Pampa Humeda in Argentina?]. / Existen relaciones entre los factores ambientales rurales y la salud reproductiva en la Pampa Húmeda Argentina?

The relationship between environmental factors and health is well known. Rural environmental influences on reproductive health have been properly proved, both in animals and humans. In Latin America, few studies have been conducted in this area. The current project is based on the description of relationships between reproductive health and environmental factors in rural populations, characterized by specific environmental characteristics. Three variables were evaluated: male-to-female birth ratio, male urogenital malformations (cryptorchidism and hypospadias), and endocrine-related cancer incidence. Five rural communities in the Pampa Humeda in Argentina were selected, and the data were compared to the national mean. Biomedical data and environmental risk factors were correlated through a geographic information system. The ratio of male to female births did not show any differences. Malformations showed very significant differences. Endocrine-related cancers showed higher incidence rates compared to the national mean, particularly in some communities. In conclusion, there is a relationship between environmental factors and reproductive health conditions in this region.

¿Existen relaciones entre los factores ambientales rurales y la salud reproductiva en la Pampa Húmeda Argentina? / Is there any relationship between rural environmental factors and reproductive health in the Pampa Humeda in Argentina?

La relación entre factores ambientales y salud es un hecho reconocido. La influencia de ambientes rurales sobre la salud reproductiva ha sido fehacientemente probada en diferentes regiones del mundo, tanto en la fauna como en humanos. En América Latina pocas investigaciones han sido realizadas en este campo. El presente proyecto se establece sobre la base de la describir las relaciones entre salud reproductiva y factores ambientales en poblaciones rurales, caracterizada por aspectos ambientales particulares. Tres variables han sido evaluadas: relación de nacimientos masculinos/femeninos; incidencia de malformaciones uro-genitales masculinas (hipospadias y criptorquidias); e incidencia de cánceres hormono-dependientes. Se seleccionaron cinco comunidades rurales de la Pampa Húmeda de Argentina, comparándose los datos obtenidos con medias nacionales. Los datos bio-médicos y las fuentes ambientales de riesgo fueron relacionados entre sí a través de un sistema de geo-referenciación. La relación de nacimientos no mostró significación. Las malformaciones presentaron una muy significativa incidencia. Los cánceres hormono-dependientes presentaron incidencia mayores a las medias nacionales, particularmente en algunas de las comunidades estudiadas. Se concluye que existe una relación entre condiciones de salud reproductiva y factores ambientales en esta región.

The relationship between environmental factors and health is well known. Rural environmental influences on reproductive health have been properly proved, both in animals and humans. In Latin America, few studies have been conducted in this area. The current project is based on the description of relationships between reproductive health and environmental factors in rural populations, characterized by specific environmental characteristics. Three variables were evaluated: male-to-female birth ratio, male urogenital malformations (cryptorchidism and hypospadias), and endocrine-related cancer incidence. Five rural communities in the Pampa Humeda in Argentina were selected, and the data were compared to the national mean. Biomedical data and environmental risk factors were correlated through a geographic information system. The ratio of male to female births did not show any differences. Malformations showed very significant differences. Endocrine-related cancers showed higher incidence rates compared to the national mean, particularly in some communities. In conclusion, there is a relationship between environmental factors and reproductive health conditions in this region.

Gastroenteropancreatic endocrine tumors: clinical characterization before therapy.

Gastroenteropancreatic endocrine tumors (GEP ETs) constitute a spectrum of tumors that arise throughout the entire body but are drawn together under a common definition based on the expression of proteins derived from granules, vesicles, or both. GEP ET characterization is dependent on the primary tumor, and encompasses various factors: the WHO classification; hormone-related symptom recognition; hormone marker measurements; screening for inherited syndromes; staging; and somatostatin receptor characterization. Hypervascularization and somatostatin expression constitute major features of endocrine tumors that affect diagnosis, imaging, and therapy. GEP ET prognosis is characterized by its diversity, including a subgroup of patients with slowly progressive disease even at the metastatic stage. Prognosis assessment is mainly based on WHO classification and staging. A second cancer and cardiovascular comorbidity might also play a major prognostic part when present. Mastery of several key points analyzed in this Review, to be applied during the diagnostic and prognostic processes, is essential for defining a tailored therapeutic management.

Menin and its interacting proteins: elucidation of menin function.

The multiple endocrine neoplasia type 1 (MEN1) gene is a tumor suppressor gene encoding a 610 amino acid nuclear protein, menin. Although mutations of the MEN1 gene are responsible for MEN 1 syndrome, the intracellular functions of menin have not been fully elucidated. Recent data suggest that interactions between menin and menin-interacting proteins have a role in physiological regulation of cell growth, control of the cell cycle and genome stability, and are potentially important in bone development and multipotent mesenchymal stem cell differentiation. Loss of these interactions might also contribute to the development of MEN 1 syndrome.

Arc and resistance welding and tumours of the endocrine glands: a Swedish case-control study with focus on extremely low frequency magnetic fields.

BACKGROUND: Mechanisms for potential effects of extremely low frequency (ELF) magnetic fields on carcinogenesis have not been identified. A potential pathway could be an interaction with the endocrine system. AIMS: To analyse occupational exposure to ELF magnetic fields from welding, and tumours of the endocrine glands. METHODS: This case-control study was based on a cohort with an increased prevalence of high exposed individuals. A total of 174 incident cases of tumours of the endocrine glands, 1985-94, were identified and data were obtained from 140 (80%) of these cases; 1692 controls frequency matched on sex and age were selected, and information on 1306 (77%) individuals was obtained. A short questionnaire was sent to a work administrator at the workplaces of the cases and controls. The exposure assessment was based on questions about job tasks, exposure to different types of welding, and exposure to solvents. RESULTS: There was an overall increased risk for all tumours of the endocrine glands for individuals who had been welding sometime during the follow up. The increased risk was attributable to arc welding; for resistance welding there was no clear evidence of an association. We found an increased risk for the adrenal glands in relation to arc welding, and for the parathyroid glands in relation to both arc welding and resistance welding. An imprecise increase in risk was also noted for tumours of the pituitary gland for arc welding. No confounding effect was found for solvent exposure, and there was no sign of biological interaction. CONCLUSION: The increased risks of endocrine gland tumours related to welding might be explained by exposure to high levels of ELF magnetic fields.

[Carcinogenic effects of single total-body irradiation with accelerated charged particles and gamma rays]. / Kantserogennye éffekty odnokratnogo obshchego oblucheniia uskorennymi zariazhennymi chastitsami i gamma-luchami.

The study deals with the frequency of tumorigenesis in the endocrine glands, skin, soft tissues and internal organs of sexually mature female rats, exposed to accelerated charged particles with low LPE, such components of cosmic radiation as 645 MeV and 9 GeV protons and 4 GeV/nuclon ions of helium. The experiment continued until the animals' natural death. We established a high frequency of endocrine and uterine tumors and a comparatively wide range of localizations in rats which had received sufficient doses of gamma radiation. There were no intestinal or renal tumors, while very few tumors of the skin and soft tissues were detected in unexposed animals.

Second primary cancers in men with prostate cancer: an increased risk of male breast cancer.

PURPOSE: Evaluation of second primary cancers provides valuable insight about etiology and shared risk factors. Studies of second primary cancers following prostate cancer conclude that overall risk of second primary cancers decreases. However, risk of bladder cancer and kidney cancer increases. We examine the risk of common and rare second primary cancers following prostate cancer in a large population based cohort to identify possible common etiological factors. MATERIALS AND METHODS: All prostate cancer cases in the Swedish Cancer Registry (135, 713) from 1958 to the end of 1996 constituted the study base. Risk (standardized incidence ratio) of second primary cancers was calculated as the ratio between observed and expected number of cancers. We used 2-tailed 95% confidence intervals (CI) to test significance. RESULTS: An overall increased risk (standardized incidence ratio 1.17, 95% CI 1.15-1.19) of second primary cancers was found but was only seen in the first 6 months of followup (ratio 3.45, 3.32-3.57). The most interesting finding was an increased risk (ratio 2.01, 95% CI 1.44-2.74) of male breast cancer. Other tumor sites with increased risk were the small intestine (standardized incidence ratio 1.39, 95% CI 1.09-1.51), skin melanoma (ratio 1.33, 95% CI 1.16-1.51) and endocrine tumors (ratio 1.41, 95% CI 1.13-1.74). CONCLUSIONS: A small but increased risk of second primary cancers following prostate cancer was found, most likely due to increased surveillance during the first 6 months after diagnosis. However, following prostate cancer there is an increased risk of endocrine related second primary cancers such as male breast cancer and carcinoids in the small intestine. To our knowledge these associations have not been reported previously, and they warrant more study.

Occupational exposure to endocrine-disrupting pesticides and the potential for developing hormonal cancers.

It is suspected that endocrine-disrupting pesticides are involved in the development of several cancer and noncancer health risks in humans and wildlife. A large number of pesticides show endocrine-disrupting activities. The potential for human and animal exposure to such pesticides is very high. Farmers, as a group, may be particularly at risk, because they are subject to higher-than-average levels of exposure to pesticides over longer-than-average periods. Recent studies have shown that the incidence of hormone-related organ cancers, or hormonal cancers, is elevated among farmers. Exposure to endocrine-disrupting pesticides, particularly to DDT and phenoxy herbicides, is suspected of involvement in some of these hormonal cancers. There is a clear need for a refined epidemiological study that focuses on specific pesticides, accurately assesses exposure, and then examines any association between pesticides and hormonal cancers among farmers.