Darko Katalinic

Metabolic Control in Type 2 Diabetes Is Associated with Sulfonylurea Receptor-1 (SUR-1) but Not with KCNJ11 Polymorphisms

BACKGROUND AND AIMS Sulfonylureas are hypoglycemic agents used for promotion of insulin secretion in type 2 diabetics (T2D). They bind to sulfonylurea receptor-1 (SUR-1), which is a functional subunit of the ATP-sensitive potassium channel (K(ATP)). The other component of the potassium channel is Kir6.2, encoded by gene KCNJ11. Polymorphisms in these genes may lead to modulated response to sulfonylurea therapy. The aim of this study was to determine a relationship between SUR-1 [exon 16 (-3C/T), exon 31 (Arg1273Arg; AGG-->AGA) and exon 33 (S1369A)] and KCNJ11 (E23K) polymorphisms and the following parameters of metabolic control in T2D: fasting plasma glucose (FPG), postprandial glucose (PPG) and HbA1c in Caucasian T2D of European origin. METHODS A total of 228 unrelated patients with T2D on sulfonylurea therapy were included in the study. Genotyping of all polymorphisms was performed by PCR-RFLP method. Biochemical parameters were determined using standard laboratory methods. RESULTS There was no difference in FPG and PPG concentration in any of the genotype subgroups. However, diabetics with wild-type C/C genotype of the SUR-1 exon 16 polymorphism had significantly lower HbA1c concentration compared to the patients with variant T/T genotype [6.9 (6.2-7.7) mmol/L vs. 8.1 (6.7-8.8) mmol/L; p=0.009]. Also, patients with wild-type G/G genotype of the SUR-1 exon 31 polymorphism had significantly higher HbA1c concentration compared to the patients with variant A/A genotype [7.8 (6.9-8.8) mmol/L vs. 6.3 (5.7-6.8) mmol/L; p<0.001]. CONCLUSIONS SUR-1 exon 16 and exon 31 polymorphisms are significantly associated with HbA1c concentration.

Clinical significance of immunohistochemical expression of cancer/testis tumor-associated antigens (MAGE-A1, MAGE-A3/4, NY-ESO-1) in patients with non-small cell lung cancer

Aims and Background This paper deals with the clinical significance of the immunohistochemical expression of MAGE-A1, MAGE-A3/4 and NY-ESO-1 antigens in patients with non-small cell lung cancer (NSCLC). Methods and Study Design The study included 80 patients with NSCLC (40 with adenocarcinoma, 40 with squamous cell carcinoma) who had undergone surgery. MAGEA1 and MAGE-A3/4 antigen expression was determined by an immunohistochemical method using the monoclonal antibody 57B, and NY-ESO-1 antigen expression was determined with the addition of the B9.8.1.1 antibody. The expression of these antigens was compared with the clinicopathological features of the tumors and the survival of the patients. Results MAGE-A1, MAGE-A3/4 and NY-ESO-1 were expressed in 17.3%, 44.4% and 18.5% of NSCLC patients, respectively. A statistically higher immunohistological expression rate of MAGE-A3/4 was found in squamous cell carcinoma (P <0.001) and a significantly higher amount of tumor necrosis was observed in tumors with MAGE-3 expression (P= 0.001), but no correlation with positive lymph nodes was found. There was a statistically significant correlation between MAGE-A1 expression in adenocarcinoma and the presence of tumor necrosis (P = 0.05). Furthermore, there was a significant correlation between NY-ESO-1 expression and positive lymph nodes in adenocarcinoma, but not in squamous cell carcinoma. No statistically significant difference in patient survival was found with regard to tumor type and the observed histopathological characteristics except tumor size. Statistically significantly better survival was found in the group of patients with adenocarcinomas who had positive expression of MAGE-A3/4 (P = 0.012). Conclusions This study demonstrated that the expression of MAGE-A3/4 antigen might be a valuable prognostic factor regarding survival in patients with NSCLC.

Symptomatic cardiac metastases of breast cancer 27 years after mastectomy: a case report with literature review - pathophysiology of molecular mechanisms and metastatic pathways, clinical aspects, diagnostic procedures and treatment modalities

Metastases to the heart and pericardium are rare but more common than primary cardiac tumours and are generally associated with a rather poor prognosis. Most cases are clinically silent and are undiagnosed in vivo until the autopsy. We present a female patient with a 27-year-old history of an operated primary breast cancer who was presented with dyspnoea, paroxysmal nocturnal dyspnoea and orthopnoea. The clinical signs and symptoms aroused suspicion of congestive heart failure. However, the cardiac metastases were detected during a routine cardiologic evaluation and confirmed with computed tomography imaging. Additionally, this paper outlines the pathophysiology of molecular and clinical mechanisms involved in the metastatic spreading, clinical presentation, diagnostic procedures and treatment of heart metastases. The present case demonstrates that a complete surgical resection and systemic chemotherapy may result in a favourable outcome for many years. However, a lifelong medical follow-up, with the purpose of a detection of metastases, is highly recommended. We strongly call the attention of clinicians to the fact that during the follow-up of all cancer patients, such heart failure may be a harbinger of the secondary heart involvement.

ABCC8 polymorphisms are associated with triglyceride concentration in type 2 diabetics on sulfonylurea therapy.

BACKGROUND The failure of therapy with oral hypoglycemic drugs leads to not only poorly regulated glycemic status, but also dyslipidemia and increased body weight and body mass index (BMI). Sulfonylureas act as insulin secretagogues by binding to the sulfonylurea receptor (SUR-1) encoded by the gene ABCC8. The aim of this study was to explore whether there is an association of ABCC8 polymorphisms SUR1 exon 16 (-3C/T), SUR-1 exon 31 (Arg1273Arg), and SUR-1 exon 33 (S1369A) with lipid concentration and BMI in type 2 diabetics on sulfonylurea therapy. MATERIALS AND METHODS This study included 251 unrelated type 2 diabetics on sulfonylurea therapy. Height and weight were measured for BMI calculation. All polymorphisms were detected by polymerase chain reaction-restriction fragment length polymorphism methods. Lipid concentrations and BMI were measured at inclusion into the study and after 6 months of follow-up. RESULTS Wild-type allele carriers for the SUR-1 exon 31 polymorphism (Arg1273Arg) had a significantly higher triglyceride (TG) concentration when compared with the carriers of two variant alleles (p=0.023). Polymorphic allele carriers of the SUR-1 exon 16 (-3C/T) polymorphism were more frequent in the subgroup of patients with the TG concentration increase after 6 months (p for genotype and allelic differences: 0.024 and 0.015, respectively). CONCLUSION ABCC8 polymorphisms in exon 16 and 31 are associated with the TG concentration in type 2 diabetics on sulfonylurea therapy.

Leptomeningeal and intramedullary metastases of glioblastoma multiforme in a patient reoperated during adjuvant radiochemotherapy

Despite huge advances in medicine, glioblastoma multiforme (GBM) remains a highly lethal, fast-growing tumour that cannot be cured by currently available therapies. However, extracranial and extraneural dissemination of GBM is extremely rare, but is being recognised in different imaging studies. To date, the cause of the GBM metastatic spread still remains under discussion. It probably develops at the time of intracranial progression following a surgical procedure. According to other hypothesis, the metastases are a consequence of spontaneous tumour transdural extension or haematogenous dissemination. We present a case of a 59-year-old woman with symptomatic leptomeningeal and intramedullary metastases of GBM who has been previously surgically treated with primary subtotal resection and underwent a repeated surgery during adjuvant radiotherapy and chemotherapy with temozolomide. Today, the main goal of surgery and chemoradiotherapy is to prevent neurologic deterioration and improve health-related quality of life. With this paper, we want to present this rare entity and emphasise the importance of a multidisciplinary approach, a key function in the management of brain tumour patients. The prognosis is still very poor although prolongation of survival can be obtained. Finally, although rare, our case strongly suggests that clinicians should be familiar with the possibility of the extracranial spread of GBM because as treatment improvements provide better control of the primary tumour and improving survival, metastatic disease will be increasingly encountered.

Cancer epidemic in Europe and Croatia: current and future perspectives

AimThe aim of this study has been to compare epidemiological indicators, incidence, and mortality from cancer in Europe and Croatia and to highlight new information, public health significance, and projects that have been implemented in terms of the prevention and early detection of malignant diseases.Subject and methodsWe used a wide range of data, ranging from those of the World Health Organization to various European epidemiological databases and the official data of the Croatian National Institute of Public Health and Croatian National Cancer Registry.ResultsCancer is a big public health problem throughout Europe since more than 6,000 Europeans are diagnosed daily, and 3,000 of them die. According to the estimates of the World Health Organization experts, around 84 million people will die from cancer in the next decade, and in 2030 the number of people suffering from cancer will go up to 12 million worldwide. Croatia is experiencing an epidemic of malignant diseases, and it is at the top according to rates for incidence and mortality from cancer in Europe. Progress in the treatment of cancer was achieved thanks to the Fund of Particularly Expensive Drugs and the start of the Prevention Programs and National Program for Early Detection of Cancer.ConclusionThe question is what we can learn from the past to influence the reduction of incidence and mortality from cancer and what measures should be taken in the future to reduce the risk of malignant diseases. Answers certainly lie in the increase of funding for the fight against cancer, in teamwork of experts professionally engaged in tumor pathology, but also in the development of national programs of early detection and prevention of cancer as well as higher public health education. That would ultimately lead to morbidity and mortality reduction.

Association of APOA5 -1131T>C polymorphism and serum lipid levels in patients with type 2 diabetes.

Significant abnormalities in lipid metabolism are frequently present in patients with type 2 diabetes mellitus (T2DM). Hypertriglyceridemia, a highly proatherogenic state, is associated with increased risk of coronary artery disease. Genetic polymorphism APOA5 -1131T>C has been recognized as a significant contributor to hypertriglyceridemia in both healthy and diabetic populations. The aim of the study was to investigate the association of APOA5 -1131T>C polymorphism with the serum levels of triglycerides, total cholesterol, high-density lipoprotein (HDL) cholesterol, and low-density lipoprotein (LDL) cholesterol in patients with T2DM. In total, 234 DNA samples from patients with T2DM were genotyped using the PCR-RFLP method. Serum lipid levels were measured using standard laboratory methods. Obtained APOA5 -1131T>C genotype frequencies were 89% (T/T) and 11% (T/C+C/C). There was no significant association between APOA5 -1131T>C genotypes and triglyceride levels (1.90 mM [1.32-2.74] vs. 1.78 mM [1.54-3.05] for T/T vs. T/C+C/C genotype; p=0.553), HDL cholesterol levels (1.30 mM [1.10-1.40] vs. 1.30 mM [1.05-1.40] for T/T vs. T/C+C/C; p=0.534), and LDL cholesterol levels (3.1 mM [2.3-3.8] vs. 3.0 mM [2.2-3.5] for T/T vs. T/C+C/C; p=0.313). Our results suggest that hypertriglyceridemia in patients with T2DM is not likely to be associated with the APOA5 -1131T>C polymorphism.