Optimization of 131I ablation in patients with differentiated thyroid carcinoma: comparison of early outcomes of treatment with 100 mCi versus 60 mCi

INTRODUCTION: The aim of this study was to compare the early outcomes between two groups of patients with differentiated thyroid carcinoma (DTC) who received 60 or 100 mCi of (131)I for remnant ablation. MATERIAL AND METHODS: 224 DTC patients with primary tumor > 1 cm of diameter or multifocal were randomised into prospective clinical trial. Patients with extrathyroideal extension of primary tumor and nodal metastases or M1 were not enrolled. 99 patients received 60 mCi, and 125--100 mCi of radioiodine as the first ablative dose. RESULTS: The effectiveness of thyroid ablation was evaluated after one year, during endogenous TSH (thyroid stimulating hormone) stimulation, and after two years during Lthyroxine therapy. Whole body scintigraphy (WBS) was performed under thyroxine withdrawal and thyroglobulin serum level was assessed. Distant micrometastases were detected in 9.8% of patients by post-therapy WBS, 11 patients in group A treated with 60 mCi and 11 in group B treated with 100 mCi. In other patients no symptoms of persistent disease were detected. At one year follow up full remission was diagnosed in 176 patients: 76 in group A and 100 in group B. The remaining ones, 13.3% and 11.2% respectively, received the second course of (131)I for remnant ablation. There were no statistically significant differences in Tg (thyroglobulin) serum level either 12 or 24 months after 131I treatment. CONCLUSIONS: Our evaluation of early efficacy of adjuvant radioiodine treatment in low risk DTC patients shows no differences between two radioiodine activities - 60 and 100 mCi in relation to thyroid ablation. Thus, the activity of 60 mCi is recommended.     

Completion total thyroidectomy in children with differentiated thyroid cancer

INTRODUCTION: The optimal surgical treatment of children with differentiated thyroid cancer remains an important point of discussion. Especially the need for completion operation is questioned in young patients. Our objective was to examine the rate of residual neoplastic disease after non radical initial operation. MATERIAL AND METHODS: From the 235 children diagnosed with differentiated thyroid cancer, 131 (56%) needed completion operation due to incomplete primary surgery. Completion operation involved thyroid bed, lymph nodes or both respectively in 91 (39%), 13 (6%) and 27 (11%) cases. Risk factors responsible for residual disease were evaluated by means of logistic regression analysis. RESULTS: Residual disease was detected in 46 (35%) of reoperated children (25% in thyroid bed and 85% in lymph node of lateral neck compartment). Sex and age did not influence the risk of residual disease in thyroid bed or lymph nodes. Papillary type of cancer and multifocality increased risk of residual disease in thyroid bed respectively by the factor of 15 (95% CI: 2-125) and 2.3 (95% CI: 1.2-4.4). Infiltration of thyroid capsule did not correlate with the risk of residual disease. Lymph node metastases in primary operation increased risk of residual disease by the factor of 16 (95% CI: 1.2-245). Histopathology, multifocality of primary tumour or infiltration of lymph node capsule did not influence the risk of residual disease in lymph nodes of lateral neck compartment. CONCLUSIONS: In children with differentiated thyroid cancer residual disease is diagnosed in about 1/3 of non radically operated cases. This high incidence justifies completion operations. The risk of residual disease is significantly increased in papillary thyroid cancer, multifocal tumours and cases with lymph node metastases.     

TUCAN, an antiapoptotic caspase-associated recruitment domain family protein overexpressed in cancer.

Caspase-associated recruitment domains (CARDs) are protein interaction domains that participate in activation or suppression of CARD-carrying members of the caspase family of apoptosis-inducing proteases. A novel CARD-containing protein was identified that is overexpressed in some types of cancer and that binds and suppresses activation of procaspase-9, which we term TUCAN (tumor-up-regulated CARD-containing antagonist of caspase nine). The CARD domain of TUCAN selectively binds itself and procaspase-9. TUCAN interferes with binding of Apaf1 to procaspase-9 and suppresses caspase activation induced by the Apaf1 activator, cytochrome c. Overexpression of TUCAN in cells by stable or transient transfection inhibits apoptosis and caspase activation induced by Apaf1/caspase-9-dependent stimuli, including Bax, VP16, and staurosporine, but not by Apaf1/caspase-9-independent stimuli, Fas and granzyme B. High levels of endogenous TUCAN protein were detected in several tumor cell lines and in colon cancer specimens, correlating with shorter patient survival. Thus, TUCAN represents a new member of the CARD family that selectively suppresses apoptosis induced via the mitochondrial pathway for caspase activation.     

Inhibition of chitosan-immobilized urease by slow-binding inhibitors: Ni, F and acetohydroxamic acid

The inhibitions by Ni²⁺ and F⁻ ions and by acetohydroxamic acid of jack bean urease covalently immobilized on chitosan membrane was studied (pH 7.0, 25°C) and compared with those of the native enzyme. The reaction progress curves of the immobilized urease-catalyzed hydrolysis of urea were recorded in the absence and presence of the inhibitors. They revealed that the inhibitions are of the competitive slow-binding type similar to those of native urease. The immobilization weakened the inhibitory effect of the inhibitors on urease as measured by the inhibition constants K_i^*. The increase in their values: 17.9-fold for Ni²⁺, 26.5-fold for F⁻ and 1.7-fold for acetohydroxamic acid, was accounted for by environmental effects generated by heterogeneity of the urease–chitosan system: (1) mass transfer limitations imposed on substrate and reaction product in the external solution, and (2) the increase in local pH on the membrane produced by both the enzymatic reaction and the electric charge of the support. By relating the K_M/K_i^* ratio to the electrostatic potential of chitosan it was found that while the reduced Ni²⁺ inhibition is mainly brought about by the potential, inhibition by acetohydroxamic acid is independent of the potential, and the acid inhibits urease in its non-ionic form. The reduction in F⁻ inhibition was ascribed to the increased pH in the local environment of the immobilized enzyme.     

Studies on histones and nuclear phosphoproteins of rat liver and Morris hepatoma.

1. The chemical composition of chromatins obtained from Buffalo rat liver and Morris hepatoma strain 5123 was investigated. 2. The presence of an additional subfraction within the very lysine-rich histone (fl) was states in both kinds of tissues. It amounted to about 8% and 5% of fl in rat liver and Morris hepatoma, respectively. 3. Nuclear phosphoproteins (phenol-soluble) from normal and tumour tissues in polyacrylamide gel in SDS showed some qualitative differences in the range of molecular weights of about 40 000 - 70 000 and over 100 000 daltons.     

Zinc and cadmium analysis in human prostate neoplasms

The objective of this study was to test the hypothesis that prostatic cancer is associated with the changes of zinc (Zn) and cadmium (Cd) concentration. Normal prostate, benign prostatic hyperplasia (BPH), and prostatic carcinoma (PCA) were analyzed for Zn and Cd by atomic absorption spectrometry. Cd level was measured using a graphite furnace and Zn level was measured by flame mode. Metal content was assessed in whole tissues and in nuclear, plasma membrane, and cytosolic fractions. An increase of Zn content in BPH, but a decrease in PCA as compared to normal tissue, was observed. Cd concentration appeared to be higher in BPH and PCA than in normal tissue. No correlation between Zn and Cd level was found in BPH specimens obtained from the same patients. Probability values ofp ≤0.05 were considered to indicate significant differences. Obtained results seem to support the hypothesis of Cd carcinogenicity and preventing function of Zn in prostatic cancer. Plasma membrane fraction corresponding to lysosomal, mitochondrial, and microsomal subcellular compartments are probably critical in Zn and Cd participation in human prostate neoplasms.     

Synthesis and cytotoxic activity of gamma-aryl substituted alpha-alkylidene-gamma-lactones and alpha-alkylidene-gamma-lactams

A series of 5-aryl-3-alkylidenedihydrofuran-2(3H)-ones 6a–g″ and 11a,b as well as 5-aryl-3-methylidenepyrrolidin-2-ones 10a–c and 12 were synthesized starting from 4-aryl-2-diethoxyphosphoryl-4-oxobutanoates 3a–g. Reaction sequence includes reduction or reductive amination of the carbonyl group, lactonization or lactamization step and finally the Horner–Wadsworth–Emmons olefination of aldehydes using thus obtained 5-aryl-3-diethoxyphosphoryl-3,4-dihydrofuran-2(5H)-ones 5a–g″ or 5-aryl-3-diethoxyphosphorylpyrrolidin-2-ones 9a–c. Furanones 6 and 11, as well as pyrrolidinones 10 and 12, were evaluated in vitro against mouse leukemia cell line L-1210 and two human leukemia cell lines HL-60 and NALM-6. Several of the obtained furanones proved to be very potent against all three cell lines with IC₅₀ values lower than 6 μM. Structure–activity relationships of these compounds, as well as 5-alkyl or 5-arylmethyl-3-methylidenedihydrofuran-2(3H)-ones 13a–e, previously obtained in our laboratory, are discussed.     

131I-MIBG therapy in the treatment of pheochromocytoma in children--own experiences

Three cases of pheochromocytoma in children/adolescents or young adults treated by 131I-MIBG are presented in this study. In one patient 131I-MIBG was administrated after ineffective surgical treatment and chemotherapy of a benign retroperitoneal tumor, whereas in two other patients 131I-MIBG therapy was carried out because of malignant pheochromocytoma dissemination. In a child with retroperitoneal paraganglioma decrease of tumor size and its fibrosis after 131I-MIBG therapy allowed radical surgery and complete recovery. In two other cases partial remission was achieved. All patients showed a good subjective response with improvement of the general condition and better blood pressure control. In two children adverse reactions such as leucopenia, hypothyroidism or hypogonadism were observed. The presented data confirm effectiveness and acceptable tolerance of 131I-MIBG treatment in pheochromocytoma, what is very important in pediatric patients.     

The CAG repeat polymorphism of the androgen receptor gene and breast cancer

Background

Genetic variants in hormone receptor genes may be crucial predisposing factors for breast cancer, and microsatellites in the androgen receptor gene (AR) have been suggested to play a role. The aim of the study was to determine the association between the length of the CAG repeats in the AR gene and the development of breast cancer. Methodology: In total, 75 breast cancer cases and 50 healthy controls were analyzed for CAG repeats in the AR gene by polymerase chain reaction and the GeneScan/Genotyping technique.

Results

CAG repeat genotypes and alleles distribution were found to be significantly different between breast cancer patients and controls (P < 0.05). While the presence of CAG repeats shorter than 22 (classified as short, S) increases the risk of breast cancer, the risk is reduced by the presence of CAG repeats longer than 22. In the group of patients with breast cancer, a high tumor stage was found to have a significant association with genotype S/S of CAG repeats in the AR gene.

Conclusion

Our results suggest that the length of CAG repeats in the androgen receptor gene is associated with the risk of developing breast cancer.     

Differences in Gene-Gene Interactions in Graves’ Disease Patients Stratified by Age of Onset

Background

Graves’ disease (GD) is a complex disease in which genetic predisposition is modified by environmental factors. Each gene exerts limited effects on the development of autoimmune disease (OR = 1.2–1.5). An epidemiological study revealed that nearly 70% of the risk of developing inherited autoimmunological thyroid diseases (AITD) is the result of gene interactions. In the present study, we analyzed the effects of the interactions of multiple loci on the genetic predisposition to GD. The aim of our analyses was to identify pairs of genes that exhibit a multiplicative interaction effect.

Material and Methods

A total of 709 patients with GD were included in the study. The patients were stratified into more homogeneous groups depending on the age at time of GD onset: younger patients less than 30 years of age and older patients greater than 30 years of age. Association analyses were performed for genes that influence the development of GD: HLADRB1, PTPN22, CTLA4 and TSHR. The interactions among polymorphisms were analyzed using the multiple logistic regression and multifactor dimensionality reduction (MDR) methods.

Results

GD patients stratified by the age of onset differed in the allele frequencies of the HLADRB1*03 and 1858T polymorphisms of the PTPN22 gene (OR = 1.7, p = 0.003; OR = 1.49, p = 0.01, respectively). We evaluated the genetic interactions of four SNPs in a pairwise fashion with regard to disease risk. The coexistence of HLADRB1 with CTLA4 or HLADRB1 with PTPN22 exhibited interactions on more than additive levels (OR = 3.64, p = 0.002; OR = 4.20, p < 0.001, respectively). These results suggest that interactions between these pairs of genes contribute to the development of GD. MDR analysis confirmed these interactions.

Conclusion

In contrast to a single gene effect, we observed that interactions between the HLADRB1/PTPN22 and HLADRB1/CTLA4 genes more closely predicted the risk of GD onset in young patients.