A. Belfiore

The role of insulin receptors and IGF-I receptors in cancer and other diseases

Abstract There is evidence, both in vitro and in vivo, that receptor tyrosine kinases play a key role in the formation and progression of human cancer. In particular, the insulin-like growth factor receptor (IGF-IR), a tyrosine kinase receptor for IGF-I and IGF-II, has been well documented in cell culture, animal studies, and humans to play a role in malignant transformation, progression, protection from apoptosis, and metastasis. In addition, the hormone insulin (which is very closely related to the IGFs) and its tyrosine kinase receptor (the IR, which is very closely related to the IGR-IR) have been documented both in vitro and in vivo to play a key role in cancer biology. Indeed, several epidemiological studies have shown that insulin resistance status, characterized by hyperinsulinaemia, is associated with an increased risk for a number of malignancies, including carcinomas of the breast, prostate, colon and kidney. Recent data have elucidated some molecular mechanisms by which IR is involved in cancer. IR is over-expressed in several human malignancies. Interestingly, one of the two IR isoform (IR-A) is especially over-expressed in cancer. IR-A is the IR foetal isoform and has the peculiar characteristic to bind not only insulin but also IGF-II. In addition, the IR contributes to formation of hybrid receptors with the IGF-IR (HR). By binding to hybrid receptors, insulin may stimulate specific IGF-IR signalling pathways. Over-expression of IR-A is, therefore, a major mechanism of IGF system over-activation in cancer. In this respect, IR-A isoform and hybrid receptors should be regarded as potential molecular targets, in addition to IGF-IR, for novel anti-cancer therapy. These findings may have important implications for both the prevention and treatment of common human malignancies. They underline the concept that hyperinsulinaemia, associated with insulin resistance and obesity, should be treated by changes in life style and/or pharmacological approaches to avoid an increased risk for cancer. Moreover, native insulin and insulin analogue administration should be carefully evaluated in terms of the possible increase in cancer risk.

Differentiated thyroid cancer in children and adolescents

In this retrospective study we ana-lyzed cancer characteristics and outcome in a consecutive series of 48 young patients (≦20 yr of age) with a differentiated thyroid cancer (DTC), observed during the period 1977–1998. In none of them was thyroid cancer related to ionizing radiation. The median age was 18.1 yr, range 7–20, and the female/male ratio was 2.5/1. Papillary thyroid cancer (PTC) occurred in 83% and follicular thyroid cancer (FTC) in 17% of cases. All patients underwent total or near total thy-roidectomy plus pre- and/or paratracheal lymph-node dissection. Surgery complication rate was low (4% permanent hypoparathyroidism; no permanent lesion of recurrent laryngeal nerve). Extrathyroid disease was present in 52% of patients with PTC and in 50% of patients with FTC, while nodal metastases were present in 62.5% of patients with PTC and in 12.5% of patients with FTC. Lung metastases occurred in 10 pa-tients with PTC (25%) and in none with FTC. Twenty-one patients required radioiodine treat-ment for metastatic disease: 11 patients for re-lapsing lymph-node metastases, 4 patients for lung metastases, 6 patients for both lymph-node and lung metastases. After a mean follow-up of 85±12 months all patients followed regularly (no.=47) were alive; 37 patients (79%) were free of disease and 10 (21%) had residual disease. Our results indicate that non-radiation-related DTC occurring in young patients often presents at an advanced stage. For this reason, although the prognosis is usually good in these patients, we believe that total or near total thyroidecto-my with lymphadenectomy is always the required initial surgical treatment.

Ultrasound scanning assessment of L-Thyroxine treatment effectiveness in a group of children with diffuse goiter

Ultrasound scanning is an accurate and objective method to assess thyroid volume; therefore it is useful to evaluate the effectiveness of L-thyroxine treatment in reducing goiter size, especially in children where clinical evaluation is inaccurate. In this prospectic study we evaluated the effectiveness of one-year L-thyroxine treatment in a group of children with nontoxic diffuse goiter coming from an area with low iodine intake. We examined 11 children (7 females, 4 males), age range 9–14 years. At clinical examination, 6 patients had a goiter classified la (according to WHO criteria), 4 had a class lb and only 1 had a class II goiter. In order to achieve an accurate goiter evaluation, the thyroid volume was determined by ultrasonic scanning with a 5 MHz linear probe before and after treatment. Patients were given a dose of L-thyroxine (1.5–2.0 µg/kg/die) in order to significantly reduce serum TSH levels (from 1.8 ± 0.6 to 0.8 ± 0.5 mU/l, mean ± SD). Patients were reexamined at 12 months of therapy and again at 10 months after therapy withdrawal. A significant reduction of the goiter volume (> 20%) was obtained in 6/11 (54%) patients, although serum TSH levels were fully suppressed only in one. The mean goiter size reduction in “responders” was −31.2 ± 9.3 % (m ± SE). After therapy withdrawal goiter size increased in the majority of cases (in 4/11, > 20%). Our study demonstrates that L-thyroxine treatment is effective in reducing goiter size in the majority of children with a diffuse goiter. Full TSH suppression is not necessary to obtain goiter volume reduction because a decrease of TSH levels to low values can already mediate a good therapeutical response. Since the majority of patients shows an increase of thyroid volume after therapy withdrawal, L-thyroxine administration should be a long term therapy.

High incidence of anti-GH antibodies in subjects treated with the GH clinical preparation available in Italy

We have characterized the GH clinical preparation available in Italy (Grorm, Serono) by gel chromatography and immunoreactivity. Only 50–60% of this preparation can be identified with the active GH monomeric form. Both higher and lower molecular weight compounds are present as well. Then, using a radioimmunoassay technique, we looked for anti-GH antibodies in 21 subjects under Grorm treatment and found them in 6 patients (28.6%). Two subjects having anti-GH antibodies with high affinity had a lower growth rate. These data suggest that anti-GH antibodies measurement is clinically useful in patients treated with this GH preparation. A more purified preparation should be used when a slowing down of the growth rate is observed in the presence of anti-GH antibodies.