Metabolic Syndrome in Childhood Cancer Survivors

Brief Overview:

The remarkable progress in developing curative therapy for childhood cancer over the last 4 to 5 decades has increased awareness of the serious cancer treatment-related late effects experienced by long-term survivors such as premature mortality early deaths, second primary cancers, organ dysfunction (heart, lung, endocrine system), fertility impairment, cognitive deficits, and reduced quality of life. Endocrine disorders, which occur in 30% to 70% of childhood cancer survivors, are among the most frequent late effects of anticancer therapy. Survivors treated with radiation and alkylating agent chemotherapy for hematological malignancies and CNS tumors are at a particularly high risk for endocrine dysfunction.

Most anticancer drugs act directly or indirectly by modifying intracellular metabolism. Therefore, high frequency of acute and late cancer treatment-related organ toxicity can result in metabolic disorders. For example, steroid-induced hypercortism blocks glycolysis and results in insulin resistance of tissues. Insulin resistance is associated with earlier manifestation of diabetes mellitus, obesity etc. The clinical sequelae of metabolic syndrome developing in childhood cancer survivors may include insulin resistance, fasting hyperglycemia, endothelial failure, obesity, dyslipidemia, hypertension, chronic fatigue syndrome, motor and behavioral disorders.

Modern genetics make it possible to create a basis for a personalized approach to the prevention of early and late toxic effects caused by anticancer therapy and the rehabilitation of the childhood cancer survivors.

Objectives:

Specific Aim 1. Evaluate the frequency and clinical features of the metabolic syndrome in childhood cancer survivors.

Hypothesis 1A: Components of the metabolic syndrome are realizing in children and adolescents at all stages of therapy of leukemia and lymphomas, can influence the development of complications and late toxic effects.

Hypothesis 1B: Initial health conditions (abnormal IBM, family history, comorbid diseases); drug's toxicity could influence to the appearance of early manifestation of metabolic syndrome.

Specific Aim 2: Evaluate the contribution of functional polymorphisms in candidate genes to metabolic syndrome outcomes among childhood cancer patients.

Hypothesis 2A: Genetic polymorphisms involved in the regulation of the insulin resistance and cancer medications during treatment contribute to the development of metabolic syndrome in childhood cancer survivors.

Specific Aim 3: Assess the extent to which genetic predictors, doses of drugs, risk factors improve the discriminatory performance of standard clinical prediction models for metabolic syndrome outcomes among childhood cancer survivors.

Hypothesis 3 A: Development of metabolic syndrome in cancer patients depends of genetic determinants and toxic effects of antitumor therapy.

Secondary Aim 1: Assess the definition of metabolic syndrome in cohort of patients of leukemia and lymphoma and survivors.

Hypothesis 1A: Episodes of triglyceridemic, insulin resistance (Hyperglycemia, HOMA>2,7, Steroid Diabetes) during the treatment could be the base evidence marker of Metabolic Syndrome in patients treated by antitumor therapy.

Hypothesis 1 B: Endothelial dysfunction as a clinical component of metabolic syndrome is responsible for cardiovascular abnormalities in cancer survivors.

Exploratory Aim 1: Assess the association of biomarkers and genetic predictors among childhood cancer survivors with therapeutic exposures (chemotherapy and/or radiation therapy) and metabolic syndrome.

Evaluation:

Eligible persons who consent to participate in this trial will be asked to do the following:

• Vital sign measurement including resting heart rate, blood pressure, height, and weight.
• A total of 12 mL of blood will be collected in 3 test tubes. Biomarker analysis will be completed by Laboratory of Dmitry Rogachev National Medical Research Center.
• A Total of 4 mL of blood in 1 test tube will be used for genotyping for the presence of polymorphic variants in genes involved in the biotransformation of xenobiotics, insulin resistance and carbohydrate metabolism in the biomolecular laboratory of Dmitry Rogachev National Medical Research Center.
• An echocardiogram and ultrasound will be performed to assess cardiac function.
• CAVI and ABI pulse wave velocity will be non-invasively measured by using the SphygmoCor VaSera VS-1500N. Arterial pressure waveforms will be recorded with a strain gauge pressure sensor placed lightly over the radial artery before and after "6-minutes physical activity".