Abstract: Anaplastic thyroid carcinoma is the most aggressive type of thyroid malignancies. Previously, we demonstrated that tumorigenicity of anaplastic thyroid carcinoma cell line ARO was significantly reduced following interleukin (IL)-12 gene transfer. We suspected that tumor target structure in ARO/IL-12 cells might be changed and such a change may make them more susceptible to be killed through mechanisms apart from natural killer-dependent pathway. To identify genes involved, we examined gene expression profile of ARO and ARO/IL-12 by microarray analysis of 3757 genes. The most highly expressed gene was cannabinoid receptor 2 (CB2), which was expressed eightfold higher in ARO/IL-12 cells than ARO cells. CB2 agonist JWH133 and mixed CB1/CB2 agonist WIN-55,212-2 could induce significantly higher rate of apoptosis in ARO/IL-12 than ARO cells. Similar results were obtained when ARO cells were transfected with CB2 transgene (ARO/CB2). A considerable regression of thyroid tumors generated by inoculation of ARO/CB2 cells was observed in nude mice following local administration of JWH133. We also demonstrated significant increase in the induction of apoptosis in ARO/IL12 and ARO/CB2 cells following incubation with 15 nM paclitaxel, indicating that tumor cells were sensitized to chemotherapy. These data suggest that CB2 overexpression may contribute to the regression of human anaplastic thyroid tumor in nude mice following IL-12 gene transfer. Given that cannabinoids have shown antitumor effects in many types of cancer models, CB2 may be a viable therapeutic target for the treatment of anaplastic thyroid carcinoma.
Abstract: OBJECTIVES: The objective of the study was to compare F-18-fluorodeoxyglucose position emission tomography (FDG-PET) with diagnostic whole body scanning (DxWBS) and post-ablation radioiodine whole body scanning (TxWBS) and to assess its prognostic value in newly diagnosed differentiated thyroid cancer (DTC) patients, hypothesizing that FDG-PET is more likely to disclose locoregional and distant metastases. PATIENTS AND METHODS: DxWBS and FDG-PET scanning were performed in 26 newly diagnosed DTC patients who underwent thyroidectomy and TxWBS in 24 cases who had radioactive iodine ablation. The results of the FDG-PET scans were correlated with the stage of the disease and the long-term outcome of DTC. RESULTS: Overall, 18 FDG-PET scans (69.2%) were positive showing a total of 40 foci while 8 scans (30.8%) were negative. The corresponding 26 DxWBS were all positive and showed a total of 47 foci. DxWBS and TxWBS showed similar foci in the 24 patients who had ablation therapy. In contrast to the FDG-PET scans that showed uptake of 26 foci (65%) outside the thyroid bed, 45 foci (95.7%) on DxWBS were in the thyroid bed while 2 foci (4.3%) were in cervical lymph nodes and no focus was seen outside the neck area (P=0.000). There was a clear correlation between the FDG-PET results, the stage of the disease and long-term outcome; seven of the eight negative FDG-PET scans were in stage 1, while all patients with disease higher than stage 1 (six patients) had positive scans. Over a median of 30 months (10-48), seven out of eight patients (87.5%) with negative FDG-PET scans were in remission compared with only eight patients (44.4%) with positive FDG-PET (P=0.04). CONCLUSIONS: In the postoperative evaluation of DTC, compared with DxWBS and TxWBS, FDG-PET scans are more likely to reveal uptake outside the thyroid bed and to correlate with the stage of the disease and long-term outcome.
Abstract: Diabetes mellitus is emerging as a major public health problem in Saudi Arabia in parallel with the worldwide diabetes pandemic, which is having a particular impact upon the Middle East and the third world. This pandemic has accompanied the adoption of a modern lifestyle and the abandonment of a traditional lifestyle, with a resultant increase in rates of obesity and other chronic non-communicable diseases. The indigenous Saudi population seems to have a special genetic predisposition to develop type 2 diabetes, which is further amplified by a rise in obesity rates, a high rate of consanguinity and the presence of other variables of the insulin resistance syndrome. We highlight the epidemiology, clinical and complications profiles of diabetes in Saudi people. Diabetes is well studied in Saudi Arabia; however, there seems to be little research in the area of education and health care delivery. This is of paramount importance to offset the perceived impact on health care delivery services, to lessen chronic diabetes complications, and to reduce the expected morbidity and mortality from diabetes.
Abstract: The mortality and neurological morbidity in heatstroke have been attributed to the host's inflammatory responses to heat stress, suggesting that anti-inflammatory therapy may improve outcome. We tested the hypothesis that a high dose of dexamethasone protects baboons against the lethal effects of heatstroke. Ten anesthetized baboons (Papio hamadryas) were assigned randomly to dexamethasone (n = 5) or control group (n = 5). Dexamethasone (2 mg/kg i.v.) was administered in four divided doses every 6 h starting immediately before heat stress and continuing during cooling. All animals were heat-stressed in a prewarmed neonatal incubator at 44 degrees C to 47 degrees C until systolic blood pressure fell less than 90 mmHg and then cooled passively at the ambient temperature. Mortality and neurological morbidity were noted, and biochemical markers of tissue injury/organ dysfunction were determined. Circulating interleukin (IL) 6 and complement components (C3 and C4) were measured sequentially. All heat-stressed animals had systemic inflammation indicated by increased plasma IL-6 and decreased C3 and C4 levels. Dexamethasone attenuated the complement system activation and maintained a higher plasma concentration of IL-6, with a significant augmentation of arterial blood pressure. Dexamethasone did not prevent the occurrence of severe heatstroke but unexpectedly aggravated significantly the tissue injury and multiorgan system dysfunction. Two animals (40%) in the control group and one in the steroid group survived (P > 0.05). Dexamethasone failed to protect the baboons from the lethal effects of heatstroke. These results do not support clinical testing of corticosteroids as beneficial in preventive or therapeutic strategies for the treatment of heatstroke in humans.
Abstract: Medullary thyroid carcinoma (MTC) is a malignant tumour of the calcitonin-secreting parafollicular C cells of the thyroid, and occurs sporadically or as a component of the multiple endocrine neoplasia (MEN) type 2/familial medullary thyroid carcinoma (FMTC) syndromes. In the present study, we investigated the frequency of mtDNA mutations in 26 MTC tumour specimens (13 sporadic and 13 familial MTC) and their matched normal tissues by sequencing the entire coding regions of mitochondrial genome. Nonsynonymous mutations were detected in 20 MTC samples (76.9%): nine out of 13 sporadic MTC (69.2%) and 11 out of 13 (84.6%) familial MTC/MEN2. Both transition and transversion types of mutations were found in the samples. Interestingly, 76.2% (16/21) of transversion mutations were found in FMTC/MEN2 patients, whereas 66.7% (12/18) of transition mutations were in sporadic MTC. Synonymous mutations were found in 12 MTC samples. In total, we identified 27 transversion mutations (21 nonsynonymous and six synonymous) in MTC. Of them, 22 (81.5%) were from FMTC/MEN2, and five (18.5%) were from sporadic MTC. The association of transversion mutation with familial MTC/MEN2 was statistically significant (P = 0.0015, binomial test). Majority of the mutations were involved in the genes located in the complex I of the mitochondrial genome, and were often resulting in a change of a moderately or highly conserved amino acid of their corresponding protein. Mitochondrial respiratory function was also compromised in a TT cell line, which carries mtDNA mutation at nt 4917 and 11,720, and in peripheral lymphocytes of MTC patients with mtDNA mutations. These data suggest that mtDNA mutation may be involved in MTC tumourigenesis and progression. Given that mtDNA mutation spectra are different between sporadic and familial MTC, different mechanisms of oxidative DNA damage may occur in the disease process.
Abstract: OBJECTIVE: To assess the diagnostic utility of [(18)F]flu-orodeoxyglucose positron emission tomography (FDG PET) in the follow-up of patients with differentiated thyroid cancer (DTC). METHODS: In this study, we used strict definitions of presence and absence of the disease and performed all FDG PET scans while the patients were not taking levothyroxine (LT4). We report the results of conventional FDG PET scans obtained during the follow-up of 50 nonselected patients with DTC (34 female and 16 male patients; median age, 40.5 years; range, 18 to 68). All FDG PET scans and measurement of thyroglobulin (Tg) levels were performed while the patients were not taking LT4 (thyrotropin>or=25 microIU/mL). Tg antibodies were negative in all patients. The initial surgical procedure was total thyroidectomy in all cases, and 26 patients underwent additional operations (2 to 4 procedures). Radioactive iodine (131I) therapy was given to 48 patients (median dose, 5,550 MBq). In 42 patients, FDG PET was used for evaluation of Tg-positive (Tg>2 ng/mL in the absence of LT4 therapy), scan-negative disease. In 8 patients, Tg was <or=2 ng/mL but other findings suggested the presence of the disease (detectable Tg in 7 cases and abnormal ultrasound findings in 3). Disease was considered present if confirmed by fine-needle aspiration, histopathologic examination of subsequent surgical specimens, or persistent elevation of Tg levels (>2 ng/mL without LT4 therapy) for >1 year. Disease was considered absent if Tg was <or=2 ng/mL and at least all the following imaging studies were negative: diagnostic radioiodine whole-body scan, chest radiography or spiral computed tomography of the chest, and high-resolution neck ultrasonography. If all these criteria were present, a positive FDG PET scan was considered a false-positive study. RESULTS: FDG PET scans were positive in 27 patients (54%) and negative in 23 (46%). FDG PET results were true-positive in 26 cases, false-positive in 1, true-negative in 7, and false-negative in 16. The sensitivity, specificity, and positive and negative predictive values were 61.9%, 87.5%, 96.3%, and 30.4%, respectively. CONCLUSION: FDG PET scanning is moderately sensitive and specific for detection of persistent or recurrent DTC.
Abstract: OBJECTIVE: Thiamine-responsive megaloblastic anemia (TRMA) is a rare syndrome characterized by diabetes mellitus (DM), anemia, and sensorineural deafness. We describe the clinical course and the molecular defect of a young woman who was diagnosed to have this syndrome. Case: The patient is an 18-year-old girl who was born to non-consanguous parents. She was noted to be deaf-mute in the first year of life. She was diagnosed with DM at the age of 9 months and with severe anemia at the age of 2 years. An extensive work up could not identify the cause. She was treated with blood transfusions every 3-4 weeks for the past 16 years. A diagnosis of TRMA was suspected and the patient was treated with thiamine hydrochloride. Hemoglobin and platelets increased to normal values after a few weeks of thiamine therapy. Diabetic control significantly improved but she had no noticeable changes in the deafness. METHODS: Peripheral blood DNA was extracted from the patient, her mother, aunt, and a healthy sister. Exons and exon-intron boundaries of the thiamine transporter gene SLC19A2 were PCR amplified and directly sequenced. RESULTS: A G515C homozygous mutation was identified in the SLC19A2 gene of the patient. This mutation changes Gly to Arg at codon 172 (G172R). The mother, an aunt, and a sister had a heterozygous G172R mutation. CONCLUSIONS: Mutations in thiamine transporter gene, SLC19A2, causes a rare form of monogenic diabetes, anemia, and sensorineural deafness. Thiamine induces a remarkable hematological response and improvement in the diabetic control but has no effect on deafness.
Abstract: CONTEXT: Defects in thyroglobulin (Tg) synthesis are one of the causes of thyroid dyshormonogenesis. Only a few mutations in the Tg gene have been described. OBJECTIVES: We describe a novel Tg gene mutation and discuss the mechanisms by which it causes dyshormonogenesis with subsequent malignant transformation. CASES: Two siblings aged 21 and 19 yr presented with recurrent goiters for which they had undergone multiple thyroid surgeries since early childhood. The older sibling was diagnosed with metastatic follicular thyroid carcinoma at age 15 yr. METHODS: The entire coding region and intron-exon boundaries of the Tg gene were amplified and sequenced from the patients. We also sequenced the boundaries of exon 5 and intron 5 from both parents. RT-PCR amplification of a cDNA fragment encompassing exons 4-6 was also performed. RESULTS: A homozygous G to A point mutation at position +1 of the splice donor site of intron 5 (g.IVS5+1G-->A) was detected in both patients, whereas a monoallelic mutation was found in their parents. RT-PCR amplification of a cDNA fragment covering exons 4-6 revealed a 191-bp fragment in the patients and 351- and 191-bp fragments in the parents. Sequence analysis of these two fragments confirmed deletion of exon 5 in the 191-bp fragment. CONCLUSIONS: Aberrant splicing occurred as a result of the g.IVS5+1G-->A mutation, which caused fusion of exons 4 and 6, resulting in the frame shift at codon position 141 and a premature stop codon at position 147 (FS141-->147X). The malignant transformation is likely a result of prolonged TSH stimulation.
Abstract: OBJECTIVE: To conduct a prospective study of the diagnostic value of features of cervical lymph nodes (large size, central location, abnormal shape, cystic changes, calcifications, and loss of echogenic hilum), assessed by neck ultrasonography (US), in patients scheduled for surgical treatment of persistent or recurrent differentiated thyroid cancer. METHODS: We studied 152 US abnormalities in 42 patients (median age, 38.5 years) who had undergone one or more neck operations, with or without radioiodine therapy, but continued to have persistent or recurrent disease, which was confirmed by fine-needle aspiration. Another surgical procedure was planned for these patients. On the day of operation, patients underwent a detailed US neck examination by an experienced radiologist. US abnormalities were plotted on a standard diagram of the neck and given specific numbers to help track them during surgical intervention and histopathologic examinations. The US features were compared with the final histopathologic diagnosis. RESULTS: Of 152 US abnormalities, 127 involved cervical lymph nodes and 25 involved other types of tissue. In univariate analysis, size, absent echogenic hilum, cystic changes, calcifications, and central location (medial to the sternomastoid muscle) of cervical lymph nodes were significantly associated with the presence of metastatic involvement. In multivariate analysis, only central location (odds ratio, 4.07; 95% confidence interval [CI], 1.64 to 10.10) and size (odds ratio, 5.14; 95% CI, 1.64 to 16.06) remained significant. The receiver operating characteristic curve for the size of lymph nodes showed a large area under the curve of 0.77 (95% CI, 0.68 to 0.85), and a size of 7.5 mm showed the highest sensitivity and specificity. Conclusion: Size and central location of cervical lymph nodes assessed by US during follow-up of patients with differentiated thyroid cancer were the most important predictors of presence of metastatic disease.
