Clinical relevance of RET variants G691S, L769L, S836S and S904S to sporadic medullary thyroid cancer

Background Based on reports of higher frequencies among patients with sporadic medullary thyroid cancer (MTC) relative to external controls, the RET (REarranged during Transfection) variants G691S, L767L, S836S and S904S have been considered disease modifiers, suggesting greater lifetime risks of MTC. Other studies, employing different external controls, failed to confirm this association. Using a complementary approach, this study aimed at exploring differences in clinico‐pathological characteristics among patients with sporadic MTC carrying no (wildtype), one (heterozygotes) or both (homozygotes) homologue RET variants in the germline, with wildtype cases acting as internal controls. Methods Included in this investigation were 150 patients with complete genetic information on G691S, L769L, S836S and S904S RET alleles operated on for sporadic MTC at a tertiary referral centre. Results Not one statistically significant dose–response relationship was identified between any RET variant (wildtype vs RET heterozygotes vs homologue RET homozygotes) and patient age at MTC diagnosis, gender, primary tumour size, extrathyroidal extension, numbers of involved and removed lymph nodes, or distant metastasis. L769L and S836S homozygotes, unlike G691S and S904S homozygotes, were either rare or absent, limiting the analyses to comparisons of heterozygosity versus wildtype. On time‐to‐event analysis, G691S, L769L, S836S or S904S carriers and noncarriers developed MTC at similar rates. Conclusions In carriers and noncarriers of the RET variants G691S, L767L, S836S and S904S, sporadic MTC appeared clinically and pathologically indistinguishable. This observation, along with the inconclusive evidence of previous association studies, calls for larger longitudinal association studies with age‐ and sex‐matched external controls and additional functional studies of RET biology.     

Inner strength in relation to age,gender and culture among old people – a cross-sectional population study in two Nordic countries

Objectives: The theoretical framework for the study was the Model of Inner Strength, and the Inner Strength Scale (ISS)developed based on the Model was used. The aim was to examine inner strength in relation to age, gender and culture among old people in Sweden and Finland.

Method: This study forms part of the GErontological Regional DAtabase (GERDA)-Botnia project that investigates healthy ageing with focus on the dignity, social participation and health of old people. The participants (N = 6119) were 65-, 70-, 75- and 80-year old and living in two counties in Sweden or Finland. The ISS consists of 20 items relating to four interrelated dimensions of inner strength, according to the Model of Inner Strength. The range of possible ISS scores is 20–120, a higher score denoting higher inner strength.

Result: The result showed that the 65-year-old participants had the highest mean ISS score, with a decrease in score for every subsequent age. The lowest score was achieved by the 80-year-old participants. Women had slightly but significantly higher mean ISS scores than men. Only small differences were found between the counties.

Conclusion: The study population came from Sweden and Finland; still, despite the different backgrounds, patterns in the distribution of inner strength were largely similar. The present study provides basic and essential information about inner strength in a population of old people.     

Effect of systemic celecoxib on human meningioma after intracranial transplantation into nude mice

Background

Meningiomas are mostly benign, but they may have a notorious tendency to recur when total resection is not possible. Systemic chemotherapeutical treatment has been largely disappointing. The treatment of meningiomas with the cyclooxygenase-2 (COX-2) inhibitor celecoxib showed inhibitory-growth effects in vitro and in vivo after subcutaneous transplantation into mouse. So far, celecoxib has never been tested in an orthotopic model of meningioma. In this work, we tested the effects of celecoxib on the growth of human benign meningiomas after transplantation into the prefrontal cortex of nude mice after confirming the inhibitory in vitro effect on these cells.

Methods

Primary cell cultures were stereotactically implanted into mice and were treated with 0, 750, or 1,500 ppm celecoxib for 3 months. The mice were then killed and blood was analyzed for celecoxib concentration. The mice brains were histologically processed for measurement of tumor volume, COX-2 expression, proliferation index (PI), intratumoral microvessel density (iMVD), and vascular endothelial growth factor (VEGF) expression.

Results

Treatment with celecoxib had no effect on tumor volume, despite the fact that we found a dose-dependent inhibitory effect on cell cultures and there was a sufficiently high celecoxib concentration in blood plasma and brain tissue. Additionally, celecoxib had neither an effect on COX-2 and VEGF expression nor on the PI and iMVD.

Conclusions

Our findings suggest that celecoxib may not be effective on meningioma growth in clinical settings. In general, these results may indicate that the effect of treatment on brain tumors should not only be tested in a heterotopic environment but also in the orthotopic location of these tumors.