Targeted therapeutic approach for an anaplastic thyroid cancer in vitro and in vivo

Anaplastic thyroid carcinoma (ATC) is among the most aggressive human malignancies, being responsible for the majority of thyroid cancer-related deaths. Despite multimodal therapy including surgery, chemotherapy, and radiotherapy, the outcome of ATC is poor. The human ATC cell line MB1, derived from tumor tissue of a 57-year-old man with thyroid cancer and pronounced neutrophilia, was established from surgically excised tumor tissue. The karyotype of the cell line shows many chromosomal abnormalities. Preclinical investigations have shown antitumor activity and effectiveness of the BRAF kinase inhibitor Sorafenib and the proteasome inhibitor Bortezomib. After establishment of the MB1 cell line these agents were applied in vitro and, showing activity in a cell culture model, were also used for in vivo treatment. Sorafenib had some clinical effect, namely normalization of leucocytosis, but had no sustained impact on subsequent tumor growth and development of distant metastasis. Molecular diagnostics of the tumor demonstrated no BRAF mutations in exons 11 and 15 concordant with a rather modest effect of Sorafenib on MB1 cell growth. Clinical benefit was seen with subsequent bortezomib therapy inducing a temporary halt to lymph node growth and a progression-free interval of 7 weeks. Our observations together with previous data from preclinical models could serve as a rationale for selecting those patients suffering from ATC most likely to benefit from targeted therapy. A prospective controlled randomized trial integrating kinase and proteasome inhibitors into a therapeutic regime for ATC is warranted. ( Cancer Sci 2008; 99: 1847–1852)     

Detection of karyotype changes in interphase cells: oligonucleotide-primed in situ labelling versus fluorescence in situ hybridization

Interphase cytogenetics is a rapidly developing technique which is usually performed by fluorescence in situ hybridization (FISH). Recently, oligonucleotide-primed in situ synthesis (PRINS) has become established as a method of labelling centromeric regions of chromosomes in metaphase spreads. We tested the suitability of PRINS in detecting the exact copy number of chromosomes 1, 3, 7 and 8 in intact interphase cells of 17 cytological preparations derived from normal and neoplastic tissues. Control procedures consisted in preparation of metaphase spreads of lymphocytes of healthy donors, conventional cytogenetics in some of the specimens, and omission of the primers or Taq polymerase from the reaction mixture. All specimens were additionally examined by FISH and analysed blind by two experienced observers. Both PRINS and FISH revealed a corresponding distribution of hybridization signals for all chromosomes examined in specimens of normal bone marrow (n = 5), normal liver cells (n = 5), three samples of acute nonlymphocytic leukaemia in which conventional chromosome analyses had shown monosomy 7 or trisomy 8, and in four hepatocellular carcinomas that displayed trisomy 1. Overall, statistical analysis revealed no significant difference in the signal distribution between the two techniques. Our results demonstrate that PRINS is as reliable as FISH for detecting chromosome copy numbers in interphase nuclei of intact cells. The PRINS method, however, is easier to perform, faster and less expensive, holding great potential for future applications in diagnostic pathology.     

Imiquimod 5% cream is an acceptable treatment option for external anogenital warts in uncircumcised males

OBJECTIVES: To determine the safety and efficacy of imiquimod (Aldara) 5% cream in the treatment of prepuce-associated warts in uncircumcised males. METHODS: An open-label study in six UK medical centres with 35 uncircumcised males with prepuce-associated warts treated with imiquimod 5% cream three times per week for up to 16 weeks. Other anogenital warts were also treated. RESULTS: Three times weekly application of imiquimod was found to be safe, with erythema as the most commonly reported local skin reaction. Forty per cent of patients had complete clearance of anogenital warts within 16 weeks. CONCLUSIONS: Imiquimod cream at a dosing regimen of three times per week, is effective and has an acceptable safety profile in the treatment of prepuce associated warts and other external anogenital warts in uncircumcised males.     

Effect of carnitine supplementation on cardiac function in hemodialyzed children

Thirteen carnitine-deficient children (mean age, 16.1 ±2.56 years) on a three-times-weekly hemodialysis program for at least 1 year, and 11 healthy age matched children were involved in the study. All the patients had stable blood pressure and hemoglobin (Hb) levels with a maintenance dose of erythropoetin and none were digitalized. The total carnitine (TC) and free carnitine (FC) plasma levels were sampled prior to hemodialysis (HD) before and after 3 months of carnitine supplementation. A free carnitine (FC) to acylcarnitine (AC) ratio less than 4 was defined as carnitine deficiency. Intravenous L-carnitine was injected at a dose of 20–4.0 mg/kg three times weekly at the end of each dialysis session for a 3-month period. Echocardiographic examination was performed the day following HD, before and after carnitine treatment. Systolic and diastolic functions of the left ventricle, including the ejection fraction, were measured. Almost all the parameters were significantly different in controls and hemodiaiyzed patients. In carnitine-deficient hemodiaiyzed patients. 3 months of L-carnitine supplementation resulted in a significant increase in blood carnitine levels and the FC/AC ratio, but this was not associated with any significant improvement of cardiac function. Furthermore no significant changes were observed in plasma triglycerides, total cholesterol or other lipoprotein parameters before or after carnitine supplementation. Although there was a moderate increase in mean hematocrit (Hct) and Hb levels, these also did not reach statistically significant levels. These results suggest that the 3 months of carnitine supplementation is not sufficient to ameliorate cardiac function or increase Hb levels in children.