Comparison of endoscopic and robotic thyroidectomy.

BACKGROUND: Endoscopic thyroidectomy is a technically challenging procedure. Robot-assisted thyroidectomy has been recently introduced and offers improved visualization and dexterity. The present study compared conventional endoscopic and robotic thyroidectomy for thyroid cancer patients in terms of perioperative outcomes and learning curve. All operations were performed by the same surgeon. MATERIALS AND METHODS: Between April 2007 and March 2010, 96 patients underwent endoscopic thyroidectomy (endoscopy group) and 163 patients underwent robotic thyroidectomy (robot group). A gasless transaxillary approach was used in both groups. The 2 groups were compared in terms of patient characteristics, perioperative clinical results, complications, and pathologic details. Learning curves for the 2 procedures were compared based on the number of cases required to reach a consistent operation time. RESULTS: Patient characteristics were similar for both groups. The mean total operation time for thyroidectomy with central compartment neck dissection was 142.7 ± 52.1 min in the endoscopy group and 110.1 ± 50.7 min in the robot group (P = .041). Both patient groups were similar in terms of pathological features including TNM stage, intraoperative blood loss, length of hospital stay, and complication rate. However, the mean number of retrieved central lymph nodes was 2.4 ± 1.9 for the endoscopy group and 4.5 ± 1.5 for the robot group (P = .004). The learning curve was 55-60 cases for endoscopic thyroidectomy and 35-40 cases for robotic thyroidectomy. CONCLUSION: Robotic thyroidectomy was found to be superior to endoscopic thyroidectomy in terms of operation time, lymph node retrieval, and learning curve. Complication rates and postoperative hospital stay were similar for the 2 procedures.

Incidence and clinical behavior of papillary thyroid carcinoma in renal allograft recipients: a single center experience.

The chronic use of immunosuppressive therapy in transplant recipients increases the long-term risk for carcinoma. However, there is insufficient knowledge regarding the incidence and biological behavior of papillary thyroid carcinomas (PTC) in renal allograft recipients. In the present study we examined the incidence and biological behavior of PTCs among 1739 patients transplanted between January 1986 and December 1999 who had been followed for a mean period of 137 months (range, 84-238 months). During the follow-up, 129 (7.4%) recipients were identified to display posttransplantation malignancies, including 12 (0.7%) with PTCs. The 6 male and 6 female patients had a mean age of 41 years (range, 23-57 years). Nine cases (incidentalomas) were diagnosed based on ultrasonographic (US) screening. Eight of those 9 were TNM stage I, 2 of the 3 clinical carcinomas were TNM stage IVa. During a mean follow-up of 94 months (range, 18-159 months), 2 (16.7%) PTC patients developed locoregional recurrence, but no patients showed distant metastases. These data showed that recipients had a higher incidence of PTC compared with the general Korean population (0.7% vs 0.02%). Posttransplantation PTC tended to show no difference in gender distribution, and was often associated with aggressive lymphatic metastasis. However, most incidentalomas showed favorable treatment outcomes. In conclusion, routine surveillance of the thyroid gland using US screening is recommended to ensure early detection, treatment, and favorable prognosis of PTC.

Cyclooxygenase-2 expression in human thyroid disease.

OBJECTIVES: Cyclooxygenase (COX)-2, which is the inducible form of the COX enzyme for prostaglandin synthesis and a key mediator of epithelial cell growth, has been shown to be up-regulated in gastrointestinal cancers. Additionally, regular intake of other non-steroidal anti-inflammatory drugs (NSAID) is known to decrease the incidence of these cancers. Therefore, the goals of the present study were to determine the possible involvement of COX-2 in human thyroid diseases. METHODS: We used immunohistochemical staining and Western blot analysis to characterize the expression of COX-2 proteins in thyroid tissues from 64 patients with thyroiditis, benign tumors, and malignant tumors with or without metastasis. Immunoreactivity scores were calculated by multiplication of the determined grades. RESULTS: COX-2 proteins were not expressed in normal thyroid tissues. However, each type of tumor tissue showed intense bands of COX-2 protein expression in Western blot analyses, and the immunoreactivity scores were 7.67+/-1.17 (SD) for thyroiditis, 7.87+/-0.9 for benign tumors, 7.53+/-1.53 for follicular cancer, 7.63+/-1.11 for papillary cancer without metastasis, and 7.17+/-1.55 for papillary cancer with metastasis. No significant differences were found in the levels of COX-2 expression between different tumor tissue types. CONCLUSION: No significant correlations were observed between clinical and/or pathological characteristics of thyroid tumors and the intensity of COX-2 protein expression. In addition, we found no difference in COX-2 protein expression between thyroiditis and thyroid tumors. Thus, up-regulation of COX-2 protein synthesis in human thyroid diseases does not appear to be of clinical significance.

Prophylactic antiemetic efficacy of granisetron or ramosetron in patients undergoing thyroidectomy.

OBJECTIVE: Thyroidectomy is associated with a high incidence of postoperative nausea and vomiting (PONV), ranging from 60% to 84%. We conducted this study to compare the antiemetic effects and safety of granisetron 20 micro g/kg and ramosetron 4 micro g/kg in patients undergoing elective thyroidectomy under standard anaesthetic technique. METHODS: One hundred and thirteen patients were randomized to receive placebo (n = 41), granisetron 20 nug/kg (n = 36) or ramosetron 4 micro g/kg (n = 36) intravenously over 2-5 minutes immediately before the induction of anaesthesia. The incidence of PONV, nausea severity score (NSS), adverse events and the need for rescue antiemetics were assessed during the first 1 hour (0-1 h) and following 23 hours (1-24 h) after anaesthesia. RESULTS: During the first hour after anaesthesia, the incidence of PONV was 36.6% for placebo, 11.1% for granisetron (p = 0.012 vs placebo) and 25.0% for ramosetron. During 1 hour to 23 hours after anaesthesia, the incidence of PONV was 51.2% for placebo, 30.6% for granisetron and 41.7% for ramosetron. There were no significant differences between the three groups. Overall (0-24 h), the corresponding incidence of PONV were 61.0%, 30.6% and 50.0%, respectively, showing a significantly lower value in the granisetron group than in the placebo group (p = 0.008). The incidence of vomiting and rescue antiemetic requirement during the first 24 hours after anaesthesia was significantly lower with the granisetron group than with placebo (p = 0.021 and 0.030, respectively). The most common adverse events in the three groups were headache and dizziness. CONCLUSION: Only granisetron 20 micro g/kg was superior to placebo for the prevention of PONV after thyroidectomy.

Neutralizing vascular endothelial growth factor activity inhibits thyroid cancer growth in vivo.

BACKGROUND: Without angiogenesis, tumor growth is limited to a few millimeters, the limit of diffusion. Vascular endothelial growth factor (VEGF) is an endothelial-specific mitogen and a major regulator of angiogenesis. METHODS: To investigate the relationship between VEGF and thyroid tumor angiogenesis, we xenografted human dermal matrix inoculated with FTC-133 cells into nude mice or directly injected FTC-133 cells subcutaneously. To block the function of VEGF, the neutralizing anti-VEGF monoclonal antibody A.4.6.1 (mAb A.4.6.1) was injected intraperitoneally twice weekly. As control, an antibody of the same isotype (Ab 5B6) or phosphate buffer saline solution (PBS) was used. To evaluate the dermal matrix as a model for angiogenesis studies, recombinant human VEGF was inoculated into the dermal matrix pocket and xenografted into mice. RESULTS: In the dermal matrix angiogenesis model, the number of blood vessels paralleled the concentration of recombinant human VEGF and was highest at 100 ng/mL. Mice that were treated with the mAb A4.6.1 developed fewer blood vessels (mean, 6.6 per HPF) than control mice (18 per HPF in Ab 5B6 and 22 per HPF in PBS; P <.01). Tumors from mice that were treated with mAb A.4.6.1 were much smaller (mean +/- SD, 0.09 +/- 0.02 gm) at 5 weeks, compared with the tumors treated with Ab 5B6 (5.38 +/- 1.15 gm) or PBS (4.0 +/- 0.72 gm; P <.001). CONCLUSIONS: VEGF is produced by the follicular thyroid cancer cell line and stimulates angiogenesis and growth of thyroid cancer. This stimulation can be blocked by mAb A.4.6.1.

Desensitization in normal and neoplastic human thyroid cell lines.

Because some papillary thyroid cancers continue to grow when thyroid-stimulating hormone (TSH) levels are suppressed, we questioned whether desensitization (i.e., a decreased cAMP response to repeat stimulation with TSH) occurs in normal and neoplastic thyroid tissue. If desensitization does occur, is it similar or different in these human thyroid cells? Normal and papillary thyroid cancer cells from the same patient were cultured as we have previously described. Normal and neoplastic thyroid tissues responded to TSH (0.01-10.0 mU/ml) by increasing cAMP production and growth in a dose-dependent manner. In normal cells there was an 11-fold mean increase in cAMP production at 4 hours, and all thyroid cultures responded. In neoplastic cells cAMP production increased from 1.5-fold to 3.0-fold with a mean 2.0-fold increase at 4 hours. In normal thyroid cells the cAMP response to a second TSH stimulus (desensitization) decreased up to 75% (range 25-75%), and desensitization occurred in all normal thyroid cell cultures. In neoplastic thyroid cells, however, the cAMP response to a second TSH stimulus decreased up to 17% (range 0-17%); and desensitization occurred in only two of the five neoplastic thyroid cell cultures. Thus when normal thyroid and neoplastic cells from the same patients were studied, greater desensitization occurred in the normal cells (75% vs. 17%). These studies document that there is greater desensitization in normal tissue than in neoplastic thyroid tissue, which may account for the increased growth of thyroid neoplasms in the presence of ever-changing low levels of TSH.

Vascular endothelial growth factor expression is higher in differentiated thyroid cancer than in normal or benign thyroid.

Vascular endothelial growth factor (VEGF) is an angiogenic factor, and its expression has been rarely demonstrated in thyroid tumors. We, therefore, investigated the expression of VEGF messenger RNA (mRNA) and production of VEGF protein in cell lines from human primary and metastatic follicular (FTC-133, FTC-236, and FTC-238), papillary (TPC-1), Hürthle cell (XTC-1), and medullary thyroid cancers (MTC-1.1 and MTC-2.2), and in human thyroid tissues (papillary, follicular, medullary, and Hürthle cell cancers, follicular adenomas, and Graves' thyroid tissue) by Northern blot, immunohistochemistry, and enzyme-linked immunosorbent assay (ELISA) studies. All thyroid cell lines expressed a 4.2-kilobase VEGF mRNA. The VEGF mRNA levels were higher in the thyroid cancer cell lines than in primary cultures of normal thyroid cells, and higher in thyroid cancers of follicular than those of parafollicular cell origin. The VEGF mRNA levels were similar in primary and metastatic thyroid tumors. Immunohistochemical staining and Northern blot analysis of the cell lines correlated positively, thus thyroid cancer cell lines stained more intensely than normal thyroid cells and follicular tumor cells more intensely than parafollicular tumor cells. Again, no difference was noted in VEGF staining between primary and metastatic thyroid tumors. Deparafinized sections of papillary, follicular, and Hürthle cell cancers also stained much stronger than those of medullary thyroid cancers, benign, or hyperplastic (Graves' disease) thyroid tissue. Thyroid cancer cell lines (XTC-1 > TPC-1 > FTC-133 > MTC-1.1) also secreted more VEGF protein as measured by ELISA than did normal thyroid cells. VEGF secretion of cell lines derived from primary and metastatic thyroid tumors were similar. VEGF mRNA is therefore expressed, and VEGF protein is secreted by normal, hyperplastic, and neoplastic thyroid tissues. The higher levels of VEGF expression in differentiated thyroid cancers of follicular cell origin suggests a role in oncogenesis.

Thyroid-stimulating hormone promotes the secretion of vascular endothelial growth factor in thyroid cancer cell lines.

BACKGROUND: Vascular endothelial growth factor (VEGF) is a vascular endothelial cell-specific mitogen secreted by some cancer cells and is a major regulator of angiogenesis. Because thyroid-stimulating hormone (TSH) promotes growth and progression of thyroid cancers, we postulated that TSH may increase the production and secretion of VEGF by thyroid cancer cells. METHODS: We examined primary cultures of normal human thyroid (NT 1.0), medullary thyroid cancer (MTC 1.1), and cell lines derived from the papillary (TPC-1), follicular (FTC-133), and Hürthle cell (XTC-1) thyroid cancer. We quantified the concentration of VEGF in conditioned medium by means of enzyme-linked immunosorbent assay. RESULTS: Cell lines derived from thyroid secrete VEGF. Basal VEGF secretion was similar in normal and thyroid cancer cells, except XTC-1, which has high basal secretion (p < 0.01). All thyroid cancer cells secrete significantly more VEGF than normal thyroid cells after TSH (10 mIU/ml) stimulation (p < 0.05). TSH stimulated secretion of VEGF in FTC-133 (8.2 ng/dl versus 18.8 ng/dl), TPC-1 (5.5 ng/dl versus 26.9 ng/dl), and MTC 1.1 (5.9 ng/dl versus 13.4 ng/dl) cell lines (p < 0.01), but not in NT 1.0 (8.4 ng/dl versus 9.9 ng/dl) and XTC-1 (25.4 ng/dl versus 31.2 ng/dl) cells. CONCLUSIONS: These results suggest that VEGF secretion is constitutively activated in some thyroid cancers and that VEGF secretion is stimulated by TSH; thus TSH may promote growth in some thyroid cancers by stimulating VEGF secretion and angiogenesis.

Surgical considerations and approach to thyroid cancer.

Patients with thyroid cancer can be safely treated by an experienced endocrine surgeon. More extensive initial surgery such as total or near-total thyroidectomy seems to decrease tumor recurrence and prolong life. When such operations can be done with minimal complications, we believe it is the treatment of choice because even low-risk patients have a 4% or 5% risk of eventually dying of thyroid cancer. If this risk of death from thyroid cancer can be decreased to 1% or 2% and the rate of serious complications is 1% or 2%, the authors believe total thyroidectomy is indicated. Most patients can be discharged within 1 day of total thyroidectomy.

Immunoprecipitation isolates multiple TSH receptor forms from human thyroid tissue.

Attempts to purify the thyroid-stimulating hormone receptor (TSHR) have been complicated by its susceptibility to proteolysis and its low level of expression in thyrocytes and many transfected cells. Controversy exists over its size and structure. Multiple, single-polypeptide forms of the TSHR (230, 187, and 95-100 kDa) have been recently identified in immunoblots of crude plasma membranes prepared from COS-7 cells transfected with rat or human cDNA, but the relationship of these receptor species to the TSHR in human thyroid tissue has been heretofore unknown. We have developed a technique for immunoprecipitation of the TSHR which employed IgG purified from a polyclonal rabbit antiserum to TSHR residues 352-366. We have used immunoprecipitation to isolate the previously characterized 95-100 kDa TSH-holoreceptor, 187 kDa intermediate, and 230 kDa precursor forms of the TSHR from plasma membrane prepared from transfected COS-7 cells and human thyroid tissue. The presence of all three forms was not altered by the addition of reducing agent to the sample buffer, demonstrating the single polypeptide structure of the TSHR. This is, to our knowledge, the first report of the purification from transfected COS-7 cells of these TSHR species identified previously only in immunoblots of crude plasma membrane, and the first report of the identification by any means of these TSHR forms in human thyroid tissue. The isolation of TSHR from human thyroid tissue requires confirmation by direct means, but promises to make the receptor available in a soluble form for studies of its structure and function.

Evaluation of thyroid function after bilateral subtotal thyroidectomy for Graves' disease--a long term follow up of 100 patients.

One hundred patients who underwent bilateral subtotal thyroidectomy for Graves' disease between January 1980 and September 1984 have been evaluated. The observation period ranged from 5 to 9 years, the average being 6.2 years. Postoperative thyroid function was evaluated with T3, T4 and TSH and compared with their clinical manifestations. Eighty-two patients became euthyroid, 14 patients had recurrence and 4 patients developed hypothyroidism. The thyroid hormone level of euthyroid patients were in an unstable state up to 5 years after the operation. Sixteen variables which might influence the postoperative recurrence and hypothyroidism were analyzed but no statistically significant factors were determined, although recurrences were found frequently in patients over 30 years, the patients with lower infiltration of lymphocytes and absent of fibrosis of thyroid tissue. The results obtained in the present study suggest that mean 6.0 gm of remnant thyroid is suitable for maintaining euthyroidism postoperatively in a majority of patients. In addition, patients should be followed closely for many years and should undergo hormonal determination periodically because recurrence and hypothyroidism can occur at 5 years or more after the operation.

Diagnostic approach to thyroid carcinoma in Graves' disease.

Among 545 surgically treated Graves' disease patients, 17 were found to have coexisting thyroid neoplasms. Of these 17 patients, 11 turned out to have thyroid carcinomas. These patients could be divided into 2 groups; Group I with a diffusely enlarged gland with a clinically palpable nodule (n = 6) and Group II without a palpable nodule (n = 5). In Group I, 4 patients were diagnosed by preoperative fine needle aspiration cytology, and the remaining 2 by intraoperative frozen-section examination. In Group II, none of the patients were suspected of any concurrent thyroid carcinoma preoperatively, and only 2 were identified by intraoperative frozen-section examination. Thus, 8 of the 11 patients were diagnosed preoperatively or intraoperatively. These observations suggest that in all patients with Graves' disease and concurrent thyroid nodules, the suspicion of associated malignancy may be raised. And also, fine needle aspiration cytology in every case of Graves' disease with a palpable nodule and intraoperative frozen-section examination of the suspicious lobe in the cases of non-palpable nodules appear worthwhile in detecting a concurrent thyroid carcinoma.

[The protective effects of monoclonal antibodies in mice from Naegleria fowleri infection].

Protective effects of monoclonal antibodies against N. fowleri were comparatively studied. BALB/c mice were treated with two types of monoclonal antibodies, Nf 2 and Nf 154, before and after the infection with N. fowleri. The mortality and mean survival times were then compared. Also, direct effect of the monoclonal antibodies on the N. fowleri trophozoites in vitro were observed. In vitro protective effects of the monoclonal antibodies were also studied in cells infected with N. fowleri. The observed results are summarized as follows: 1. Among mice pretreated twice before the infection with monoclonal antibody Nf 2(McAb Nf 2), only 15.8% were killed, and the mean survival time was 17.7 days. This was not much different from the mice pretreated once, as the mortality and mean survival time were 16.7% and 17 days. Those effects were compatible with monoclonal antibody Nf 154(McAb Nf 154). The above findings contrast with the mortality and mean survival time of the control mice, which were 22.7% and 14.6 days respectively. 2. Mice which received twice the McAb Nf 2 following N. fowleri infection incurred a 19.4% mortality rate with 13.6 days survival time; 17.9% and 15.8 days with on time administration, in contrast to the 25% and 14.6 days in the control group. 3. Marked agglutination effect of McAb Nf 2 or McAb Nf 154 were observed on N. fowleri trophozoites. 4. When N. fowleri trophozoites were treated with McAb Nf 2 or McAb Nf 154 combined with comments, the proliferation rate was more significantly suppressed than in that the control. 5. N. fowleri trophozoites treated with McAb Nf 2 or McAb Nf 154 showed an increased number of swollen mitochondria, disfigured cisternae, lipid droplets, and osmiophilic granules in the cytoplasm. 6. A remarkable protective effect of monoclonal antibodies was noticed in CHO cells infected with N. fowleri. More than 90.6% of the infected CHO cells survived, contrasted with 27% of untreated cells. The overall results in this study suggest that N. fowleri treated with monoclonal antibodies against N. fowleri reduce the mortality and prolong the survival time of the mice when the antibodies are administered before the infection. The protective effect of the monoclonal antibodies is surmised being caused by agglutination of the trophozoites.

Thymidine labeling index in breast tumors.

The relationship between primary tumor proliferative activity and clinical and pathologic characteristics was analyzed in relation to menopausal status in 32 patients with malignant or benign breast disease. The thymidine labeling index (TLI) showed significantly higher median values in the cancer patients (3.48 per cent) than in the patients with benign diseases (1.02 per cent). TLI was not significantly affected by delayed incubation at room temperature for about 1 hour. In the breast cancer patients, TLI did not significantly correlate to tumor size, the presence of axillary lymph node metastasis or pathologic nuclear grading. The only significant difference was limited to the breast cancer patients without axillary lymph node metastasis in relation to menopausal status; the TLI in the premenopausal patients (5.10 per cent) was significantly higher (p less than 0.05) than that in the postmenopausal patients (2.28 per cent). These data thus suggest that among premenopausal patients without axillary lymph node metastasis, those with a high TLI could be potential candidates for adjuvant chemotherapy.