Oncodiabetology II. Antidiabetics and cancer prevention / Onkodiabetológia II. Antidiabetikumok és rákmegelozés

The number of patients with type 2 diabetes is increasing worldwide. In Hungary, the prevalence of known diabetic adults exceeds 9.1%, causing increased economical and medical burden to the society. It is obvious that there is a considerable urge to develop novel, safer and more efficient antidiabetic drugs. Therefore, studies have been focusing on the beneficial or detrimental side effects of antidiabetic drugs besides their general metabolic effects. Every anti-diabetic agent has an indirect anti-tumor effect as a consequence of lowering blood glucose levels and controlling carbohydrate, protein and lipid metabolism. In addition, most agents have their own direct antitumor effects, on the other hand, some may play a negligible role in cancer promotion. While the latter possibility is based mainly on pre-clinical, experimental data or on short-duration clinical studies, the informations about the safety of antidiabetic drugs are verified by large-scale, randomized, multicenter, placebo-controlled trials. Nowadays, metformin is the only drug that has been shown to reduce cancer risk in a variety of tumor localizations in monotherapy or in combination with other antidiabetic agents and insulins, and even in combination with certain cytostatics and biological therapies. The available data about the role of other antidiabetics in tumor prevention are less clear or insufficient. Here, we review the available ­ sometimes contradictory ­ literature about the relationship of tumor and antidiabet ics, verifying the safety of antidiabetics. Here, we propose that in the future tumor-specifically optimized antidiabetic treatment may play a role in tumor prevention or even in specific oncotherapy in patients with or without diabetes.

Oncodiabetology III. The relationship of antineoplastic therapies and carbohydrate metabolism / Onkodiabetológia III. Az antineoplasztikus terápiák és a szénhidrát-anyagcsere viszonya

The epidemiological indicators of malignant diseases and diabetes are changing similarly, as lately both have been dynamically increasing worldwide. They occur usually in the same patient synchronously or metachronously, because of their common metabolic and molecular background. Consequently, in more and more cases they require common treatment. That has led to a new science, called oncodiabetology, the main purpose of which is to optimize the combination of antineoplastic and antidiabetic therapies. Regarding the antineoplastic agents, their complex influence on metabolism has to be considered, especially diabetogenic side effects inducing insulin-resistance and decreasing insulin production. According to antidiabetic agents' role in preventing tumors, diminishing toxicity of cytostatic drugs, and promoting the breakthrough of chemoresistance should be considered. In this study, we investigate the contexts of antineoplastic agents' efficiency and the glucometabolism of the organization, the characteristics of oncotherapy in patients suffering from malignant disease and diabetes, and review those cytostatic agents, having massive diabetogenic adverse effects. We describe the properties and subtypes of secondary diabetes, thoroughly discuss the specific characteristics of hyperglycaemia and diabetes caused by malignant diseases and antineoplastic treatments, especially pancreatic diabetes. In the end, we attempt to determine the proper place and role of oncodiabetology in the treatment of patients suffering from malignancies. During our investigation, we assessed the effects on glucometabolism of the recently used classic cytostatics, molecularly targeted therapies and different endocrine manipulations treating malignancies. We reviewed the schedules and scientific background of almost 300 medicines for this aim. We established that every third antineoplastic agent influenced glucometabolism adversely. We report our further observations in our next reviews.

Oncodiabetology I. Metabolic and molecular relationships between cancer and diabetes / Onkodiabetológia I. Metabolikus és molekuláris összefüggések a rosszindulatú daganatok és a cukorbetegség között

In the recent decades, numerous studies have investigated the metabolic and molecular links between carbohydrate metabolic disorders and cancer, raising potential anti-tumor therapies. Based on epidemiological, preclinical, and clinical studies, now we know that advanced diabetes is a distinct risk factor of the development of many tumors, and even prediabetes may lead to the increased risk of developing cancer. Nowadays we can also state that the relationship is also present vice versa. It is a well-known fact that malignancies cause metabolic and molecular changes in the host over time resulting in an insulin-resistant state, characteristic of early diabetes. The tumor-induced insulin resistance may lead to the development of secondary diabetes in some patients with cancer. Furthermore, the diabetogenic ef-fect of the present anticancer therapies may worsen the metabolic condition. In recent years, research exploring the molecular causes of the correlation between malignancies and type 2 diabetes mellitus has highlighted the central role of RAS and PI3K signaling pathways. The altered function of these pathways significantly effects cell cycle, cellular metabolism, cell growth and proliferation, thus modifying cell survival, leading to tumorigenesis and tumor progres-sion and to insulin resistance as well. Without understanding the correlations between IGF receptors, RAS and PI3K signaling pathways the underlying molecular mechanism cannot be understood. Therefore, here we focus on these molecular mechanisms after a brief description of the most important metabolic connections between cancer and diabetes.

[Hashimoto encephalopathy]. / Hashimoto-encephalopathia.

The authors present a case report and review the literature on Hashimoto encephalopathy. The onset of the disease may be marked by focal and then progressively generalized seizures or other neurological symptoms, but a cognitive decline or various psychiatric symptoms may also emerge. High levels of anti-thyroid peroxidase antibodies and/or anti-thyroglobulin antibodies are present in the serum. Corticosteroid treatment usually results in an improvement of symptoms. The syndrome is frequently overlooked and, therefore, the authors strongly recommend testing serum thyroid autoantibodies in cases with encephalopathy of unknown origin independently on the presence of thyroid disease in the patient or family history. The importance of long-term immunosuppressive treatment should also be stressed.

Amplification of thymosin beta 10 and AKAP13 genes in metastatic and aggressive papillary thyroid carcinomas.

Papillary thyroid carcinoma (PTC) is the most common well-differentiated thyroid cancer. Although the great majority of the cases exhibit an indolent clinical course, some of them develop local invasion with distant metastasis, and a few cases transform into undifferentiated/anaplastic thyroid carcinoma with a rapidly lethal course. To identify gene copy number alterations predictive of metastatic potential or aggressive transformation, array-based comparative genomic hybridization (CGH-array) was performed in 43 PTC cases. Formalin-fixed and paraffin-embedded samples from primary tumours of 16 cases without metastasis, 14 cases with only regional lymph node metastasis, and 13 cases with distant metastasis, recurrence or extrathyroid extension were analysed. The CGH-array and confirmatory quantitative real-time PCR results identified the deletion of the EIF4EBP3 and TRAK2 gene loci, while amplification of thymosin beta 10 (TB10) and Tre-2 oncogene regions were observed as general markers for PTC. Although there have been several studies implicating TB10 as a specific marker based on gene expression data, our study is the first to report on genomic amplification. Although no significant difference could be detected between the good and bad prognosis cases in the A-kinase anchor protein 13 (AKAP13) gene region, it was discriminative markers for metastasis. Amplification in the AKAP13 region was demonstrated in 42.9% and 15.4% of the cases with local or with distant metastasis, respectively, while no amplification was detected in non-metastatic cases. AKAP13 and TB10 regions may represent potential new genomic markers for PTC and cancer progression.