Blood group antigens: molecules seeking a function?

The blood group antigens have been dismissed by some researchers as merely 'icing on the cake' of glycoprotein structures. The fact that there are no lethal mutations and individuals have been described lacking ABO, H and Lewis antigens seems to lend weight to the argument. This paper reviews the research which suggests that these antigens do indeed have function and argues that blood group antigens play important roles in modulation of protein activity, infection and cancer. It explores the evidence and poses questions as to the relevance and implications of the results.     

Brain metastases in patients with differentiated thyroid carcinoma

We present a retrospective review of six patients who developed brain metastases in our series of 649 with differentiated thyroid carcinoma seen at the Royal Marsden Hospital between 1936 and 1991. Prognosis was poor, with survival 1-19 months from the diagnosis of brain metastases in five patients. One patient remains alive at 18 months. A dosimetric approach may help to individualize and optimize treatment.     

Outcome of differentiated thyroid cancer in Graves' patients

The clinical behavior and outcome was evaluated in 21 nonoccult differentiated thyroid carcinomas occurring in Graves' patients during the period 1982-94 and compared with that of matched tumors occurring in euthyroid controls (n = 70). At surgery, patients with Graves' disease showed distant metastases more frequently than euthyroid patients (3/21 = 14.3% vs. 1/70 = 1.4%, P = 0.0556). Graves' patients also showed a significantly higher cumulative risk of recurrent/progressive distant metastases or total adverse events (odd ratios = 3.14 and 2.07, respectively) as compared with euthyroid patients. At the last follow-up visit, persistence of distant metastases was also more frequent in the Graves' group (P = 0.007), although the cumulative individual dose of radioiodine administered was higher than in the control group (median dose = 805 mCi vs. 350 mCi). Two patients died in the Graves' group vs. none in the control group. Circulating thyroid stimulating antibodies were present in all patients but one and persisted as long as signs of disease were evident. These findings indicate that differentiated thyroid carcinomas in patients with Graves' disease are more aggressive than those occurring in matched euthyroid controls and should, therefore, be managed accordingly.     

Tumor vascularity predicts recurrence in differentiated thyroid carcinoma

Insulin treatment is reportedly associated with the transient progression of retinopathy, possibly with the development of macular oedema in middle-aged Type 2 diabetic patients. The purpose of this study was to investigate the effect of insulin treatment on eye-grounds in elderly (> 65-year-old) Type 2 diabetic patients with secondary failure of oral antidiabetic-drug therapy. Eye examinations were performed in 37 patients randomized to insulin (n = 19) or sulphonylurea (n = 16) treatment and re-investigated after one year. Insulin treatment reduced HbA1c from 9.3% to 7.3% (p < 0.001) after one year. In the sulphonylurea-treated group, HbA1c did not change (9.1 vs. 9.3%). At the start, 65% of the patients had retinopathy, and after one year progression was noted in 7/35 patients (20%; 5 insulin- and 2 sulphonylurea-treated). In the insulin-treated group, the 5 patients with progression had higher initial fasting blood-glucose levels than other patients in the group (15.8 vs 13.1 mmol/L, p < 0.05). Initial HbA1c levels did not differ between the groups (9.8 vs. 9.1%, n.s.), nor the reduction of HbA1c levels during treatment (2.2 vs. 1.3% n.s.). Thus, diabetic retinopathy in this study was common among elderly Type 2 diabetic patients. The progression of retinopathy may in fact be associated with insulin treatment or improvement of metabolic control.     

Radiolabeled somatostatin analog scintigraphy in differentiated thyroid carcinoma

After intravenous administration of a radiolabeled somatostatin analog (octreotide), an image of the thyroid gland is frequently observed; few data are available, however, on somatostatin receptors in epithelial thyroid cells assessed in vitro and on images of differentiated thyroid carcinoma (DTC) with pentetreotide scintigraphy. METHODS: In four patients with metastatic thyroid carcinoma, whole-body scintigraphy was performed 4 to 48 hr after injection of 110 MBq of 111In-pentetreotide. The results were compared to data obtained with other imaging modalities, including scintigraphy performed after administration of a therapeutic dose of 131I. RESULTS: There were positive foci in distant metastases on 111In-pentetreotide scintigraphy. Pentetreotide scintigraphy was positive in two patients with an "insular" form of DTC, one of whom had a positive (faintly) 131I scan. Of the other two patients with papillary DTC without radioiodine uptake, only one exhibited a certain degree of pentetreotide scintigraphy positivity in distant metastases. CONCLUSION: These results show promise for exploration of insular thyroid carcinoma and suggest that these carcinomas may possess functional differentiation features, including somatostatin receptors.     

Surgery of differentiated cancer of the thyroid

A retrospective study on patients with differentiated thyroid carcinoma operated on at the 3rd Department of General Surgery of the University "La Sapienza" of Rome from 1970 to 1996 was performed. In 709 patients total thyroidectomy was performed as the minimal procedure acceptable, while 19 patients had subtotal thyroidectomy out of necessity. A functional ipsilateral or bilateral lymphnectomy of the neck was performed in 256 cases. This wider operation is indicated in the presence of metastatic lymph nodes and on principle in patients older than forty-five years in which at least another risk factor is present. Long term follow-up (12 years) was assured in 302 patients and the survival rate was 92% independently from the histotype (papillary or follicular). The survival rate of a group of 120 patients (80 with papillary and 40 with follicular carcinoma) was analyzed in relation to the risk factors. This group analysis demonstrated a very low mortality rate in patients with low risk index and an increased rate in patients with a high risk index.     

Outcome of differentiated thyroid cancer diagnosed in pregnant women

The clinical features and outcome of thyroid cancer in 61 pregnant women (mean age, 26.0 +/- 5.9 SD yr) and in 528 female, age-matched controls who were not pregnant (mean age, 26.3 +/- 5.9 SD yr) were compared. Median follow-up was 22.4 and 19.5 yr [P = not significant (NS)] in the two groups, respectively. The thyroid nodule was asymptomatic and discovered on routine examination more often in the pregnant women (74%) than in controls (43%, P < 0.001); other clinical and tumor features were similar in the two groups. Most of the pregnant women underwent thyroidectomy after delivery (77%) or during the second trimester of pregnancy (20%). Near-total thyroidectomy was done in 43 (73%) of the pregnant women and 265 (59%) of the controls (P = NS), and nearly the same proportion of both groups (30% and 25%, respectively) were treated with 131I postoperatively. Outcome in the pregnant women and controls, respectively, was: cancer recurrence 9 (15%) and 107 (23%, P = NS); distant recurrences 1 (2%) and 12 (3%, P = NS), and cancer deaths 0 and 6 (1.2%, P = NS). Outcomes were similar when surgery was done during or after pregnancy, despite a longer delay in treatment of the latter (1.1 +/- 1.0 vs. 16.1 +/- 19.7 months, P < 0.001). This study suggests that the prognosis of differentiated thyroid cancer is the same in pregnant women and nonpregnant women of the same age, and that the diagnosis and treatment of thyroid cancer occurring during pregnancy can be delayed until after delivery in most patients.     

"High-dose" radioiodine therapy in advanced differentiated thyroid carcinoma

There is yet no consensus concerning the appropriate regimen of the application of [131I]sodium iodine (Nal) activities to patients suffering from advanced differentiated thyroid carcinoma. We report on a total of 167 applications of [131I]Nal, including 78 applications of 11.1 GBq. Response to high-activity radioiodine therapy (RIT) is correlated to the course of the disease as well as to the reaction of thyreoglobulin and acute/subacute side effects of radiation. METHODS: Following radioablation of thyroid remnants using 1.85 to 3.7 GBq[131I]Nal, 26 patients with advanced differentiated thyroid carcinoma (follicular, 11; papillary, 4;mixed-cell thyroid carcinoma, 11) were treated with repeated activities of 11.1 GBq[131I]Nal. Initial tumor staging according to UICC showed T4 in 54%, T3 in 19%, T2 in 19% and was not obtained in 8%. Differentiated thyroid carcinoma was multifocal in 23% of patients. Applied accumulated activities ranged from 14.8 to 99.9 GBq with a mean of 55.5 GBq per patient. RESULTS: Mean post-diagnostical follow-up was 73 mo, mean follow-up after diagnosis of metastatic spread was 48 mo. Follicular thyroid carcinoma remained as stable disease in 7 of 11 patients, 6 of whom showed metastatic disease after a mean of 20 mo, and only 1 complete remission was achieved using high-dose therapies, with progressive disease in the remaining patients. Overall, 73% of follicular thyroid carcinoma had progressive disease without major response to high-activity RIT. In contrast, only 20% of papillary thyroid carcinoma/mixed-cell thyroid carcinoma showed progressive disease, and complete remission was achieved in 47% of patients. Pulmonary and lymph node metastases in the majority of patients showed good response to therapy, whereas local recurrences and bone metastases showed minor reactions to RIT. After low-activity therapies 8% of patients showed WHO grade I hematotoxic reactions. After high-activity therapies, 38% of patients had WHO I, 8% WHO II and one patient had WHO III toxicity (4%). CONCLUSION: Use repetitive high-activity RIT with a maximum of 44.4 GBq applied during 1 yr and a maximum of 99.9 GBq accumulated activity resulted in a significant increase of hematotoxicity. However, during the follow-up period (mean, 4 yr), no clinical symptoms possibly related to low blood counts were seen in patients with advanced differentiated thyroid carcinoma. Initiation of high-activity RIT in reaction to metastatic tumor outspread to achieve complete remission was found to be useful in treating papillary thyroid carcinoma and mixed-cell thyroid carcinoma, but only in a minority of follicular thyroid carcinoma patients.     

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.     

The role of genetic factors in the pathogenesis of thyroid neoplasms

This paper summarizes the current knowledge on the role of genetic factors in the development of thyroid neoplasms. The introduction of the methods and concepts of molecular genetics (as, e.g. recombinant DNA technology) have elucidated etiopathogenesis of the majority of thyroid tumours and, in the future, can make the diagnosis easier. Mutations of genes involved in the control of cellular growth and/or differentiation (ras, c-myc, RET, met) affect the development of thyroid neoplasms. Loss of heterozygosity (LOH) may suggest the presence of tumor suppressor genes and has been reported in thyroid follicular carcinomas. Activation of tyrosine kinase, whether by specific oncogene amplification or by rearrangement, appears to be highly specific for the transformation of thyroid follicular cells into papillary tumours. Cytogenetic studies have shown frequent clonal abnormalities in thyroid follicular adenomas and carcinomas.     

Chromosome aberrations in patients with papillary thyroid cancer and other neoplasms

BACKGROUND: The very low frequency of rhabdomyosarcoma (RMS) of the extrahepatic biliary tree has impeded the development of a standardized form of treatment. PROCEDURE: Based on the good response of embryonal RMS to chemotherapy, we used a multi-drug protocol as the initial treatment of a 3-year-old girl after obtaining adequate transparietohepatic biliary drainage. The treatment achieved complete remission. Later conservative laparoscopic surgery revealed only residual scar tissue. The patient is alive and well 1 year after remission. DISCUSSION AND CONCLUSIONS: Management of this difficult tumor using modern less invasive techniques for diagnosis and treatment, with the help of preoperative chemotherapy, prevented extensive damage to the biliary tree and allowed complete recovery.     

The changing role of radioiodine in the management of differentiated thyroid cancer

Craniosynostosis occurs in one out of 2,000 births. It results in primary skull deformations requiring surgical repair, in infants with a body weight of less than 10 kg. Pure craniosynostosis is the most frequent situation, where the risk for cerebral compression during brain development is the lowest. Therefore the aim of surgical correction in this case is mainly cosmetic. Conversely, in syndromic craniosynostosis, associated malformations are more common and cerebral, visual and respiratory consequences of complex facio-craniosynostosis are usually severe. Current surgical techniques consist of a total skull vault reconstruction which carry a high risk of sudden and major blood losses. Intraoperatively, whatever the type of craniosynostosis, mean blood losses corresponding to 90% of estimated red cell mass have to be anticipated. These blood losses vary according to the type of skull deformation and the type of surgery. Accurate evaluation is usually difficult and must be based more on calculation of red cell mass variations than on simple monitoring of surgical drainage. Invasive haemodynamic monitoring is always required. To reduce the amount of homologous blood transfusion, peroperative haemodilution seems to be the most suitable technique, due to unresolved technical difficulties in autotransfusion practice in infants. Severe facial deformities are associated with chronic hypoxaemia and cerebral compression representing major risk for these children in poor condition undergoing such major surgical procedures. With experienced teams, this high-risk surgery carries a low peroperative mortality (less than 1%) and morbidity rate. The latter includes essentially transient peroperative hypotension. The excellent final cosmetic and functional results justify the practice of this surgery in children with a bodyweight of less than 10 kg.     

Low-risk differentiated thyroid cancer: the need for selective treatment

By means of an electron microscopic study of the intestine in young rats infected with Cryptosporidium parvum we observed a mass migration of immunocompetent cells of the host (eosinophils, neutrophils and macrophages) into the lumen of intestine. Some lymphocytes were also observed. Immunocompetent cells (except lymphocytes) included inside phagosomes with different endogenic states of C. parvum. Macrophages with typical extracytoplasmic parasitophorous vacuoles formed by C. parvum were also observed in the intestine lumen. Almost all stages of C. parvum could be observed on a surface of such macrophages. However, we did not find in lamina propria of intestine villi any macrophages with parasites. The place of macrophages infection is unknown. We suggest that surviving of C. parvum in macrophages is principally possible.     

Cervico-mediastinal recurrences of differentiated thyroid cancers: value of MRI

AIM: The aim of this study was to evaluate the ability of MRI to detect recurrent differentiated thyroid carcinomas developed in the neck or the upper mediastinum. RESULTS: MRI was performed in 25 patients, and was compared in 5 cases with surgery. In 20 cases it was compared with I-131 scintigraphy (100 mCi in 14 cases and 5 mCi in 6 cases). The sensibility, specificity and overall accuracy of MRI was respectively: 100%, 66.6%, 82.6%. COMMENTARY: MRI is a good technique to detect recurrent thyroid carcinomas. It is specially interesting to investigate patients with a biological suspicion of recurrence and a negative scintigraphy. Mediastinal localisations that cannot be detected by US can be detected by MRI.