V. Pezzino

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.

High prevalence of differentiated thyroid carcinoma in acromegaly

Objective Acromegaly is a chronic disease caused by increased GH secretion and associated with a greater risk of developing both benign and malignant tumours. In the present study we evaluated the prevalence of thyroid disorders and thyroid malignancies in a series of acromegalic subjects.

HMGA1 inhibits the function of p53 family members in thyroid cancer cells

HMGA1 is an architectural transcription factor expressed at high levels in transformed cells and tumors. Several lines of evidence indicate that HMGA1 up-regulation is involved in the malignant transformation of thyroid epithelial cells. However, the mechanisms underlying the effect of HMGA1 on thyroid cancer cell phenotype are not fully understood. We now show that in thyroid cancer cells, HMGA1 down-regulation by small interfering RNA and antisense techniques results in enhanced transcriptional activity of p53, TAp63alpha, TAp73alpha, and, consequently, increased apoptosis. Coimmunoprecipitation and pull-down experiments with deletion mutants showed that the COOH-terminal oligomerization domain of p53 family members is required for direct interaction with HMGA1. Moreover, inhibition of HMGA1 expression in thyroid cancer cells resulted in increased p53 oligomerization in response to the DNA-damaging agent doxorubicin. Finally, electrophoretic mobility shift assay experiments showed that the p53-HMGA1 interaction results in reduced DNA-binding activity. These results indicate a new function of HMGA1 in the regulation of p53 family members, thus providing new mechanistic insights in tumor progression.

Growth Hormone Levels in Diabetes: Correlation with the Clinical Control of the Disease

We carried out contemporaneous daytime blood sugar and growth hormone (HGH) determinations in eight juvenile and six middle-aged diabetics under both poor and good metabolic control. A continuous blood sampling technic was used. The following results were obtained: 1. HGH values in poorly controlled diabetics were higher and more fluctuating than in normals of a corresponding age. 2. After good control was reached, a significant HGH decrease was observed in all patients but one. In this condition HGH levels were normalized in middle-aged diabetics but not in juvenile ones. In the latter group HGH values, even if decreased, were persistently higher than in controls of the same age. 3. No difference was observed between newly diagnosed diabetics and patients known to have had diabetes for some years. Our data support the suggestion that HGH abnormalities in diabetes are a consequence of the metabolic disturbance.

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.

Usefulness of Recombinant Human Thyrotropin in the Radiometabolic Treatment of Selected Patients with Thyroid Cancer

Treatment of persistent/recurrent differentiated thyroid cancer is based on surgery, when feasible, and malignant tissue ablation by 131I administration. This procedure requires levothyroxine withdrawal to obtain high levels of endogenous thyrotropin (TSH) to stimulate radioactive iodine uptake by the malignant tissue. Levothyroxine withdrawal may cause severe adverse effects and complications in patients with concomitant illness or advanced metastatic disease. The recent availability of recombinant human thyrotropin (rhTSH) allows diagnostic whole-body scan (WBS) and thyroglobulin testing without levothyroxine withdrawal. We describe six patients with metastatic differentiated thyroid cancer (DTC) and concomitant illness in whom the use of rhTSH was effective in preventing the complications that patients had previously experienced during hypothyroidism consequent to levothyroxine withdrawal. Our results indicate that rhTSH can be particularly advantageous to avoid signs and symptoms of hypothyroidism and complications because of associated diseases in view of 131I treatment of DTC metastases in selected cases in which levothyroxine withdrawal may be dangerous. Its efficacy to treat advanced metastatic disease should be further investigated.

A radioimmunoassay for human thyroglobulin: methodology and clinical applications

Abstract. A specific double‐antibody radioimmunoassay with a sensitivity of 2.5 ng/ml has been developed for measuring thyroglobulin (Tg) in human serum. As endogenous anti‐Tg antibodies in serum interfere in the assay, only sera with a negative tanned red cell (TRC) test are suitable for analysis. Tg was detectable in 84.7% of the euthyroid subjects, with a mean value of 6.1 (values ranging from nondetectable to 43.0 ng/ml). Values were significantly higher in women than in men. Tg release by the thyroid appears to be under pituitary control, as suggested by TSH stimulation and T3 suppression tests. Elevated Tg levels were found in hyperthyroidism, simple goitre, and differentiated thyroid carcinoma. The significance of circulating Tg and the possible application of the Tg RIA are discussed.

A diffuse sclerosing variant of papillary thyroid carcinoma: clinical and pathologic features and outcomes of 34 consecutive cases.

BACKGROUNDnThe diffuse sclerosing variant of papillary thyroid carcinoma (DSPC) is a relatively rare variant of papillary thyroid cancer. Large studies of patients with DSPC have been infrequently performed, and controversy still exists concerning some DSPC features and outcomes. The aim of the present study was to retrospectively evaluate the clinicopathologic features and outcomes in a series of 34 consecutive patients with DSPC and to compare them with a larger group of 245 consecutive patients with the classic variant of papillary thyroid carcinoma (cPTC) that were evaluated in the same period.nnnPATIENTS AND METHODSnClinical and histological features (sex, age, tumor size,multifocality, bilaterality, extra thyroid extension, and local and distant metastases) were recorded in all patients, as well as any persistent or recurrent disease and the patients disease status at last observation. Patients with cPTC were classified as either low (122) or high risk (123). DSPC and high-risk patients were all treated with the same protocol, including ¹³¹I treatment. All patients were included in a Cox regression model analysis to investigate the effect of each variable on the hazard ratio.nnnRESULTSnAs expected, multifocality, bilaterality, and extra thyroid extension were more frequently noted at presentation, and the pT1 category of TNM classification was less frequently noted in DSPC and high-risk patients with cPTC compared with low-risk patients with cPTC. No significant difference was found between patients with DSPC and those with high-risk cPTC, except that extra thyroid extension was found more frequently in the patients with DSPC. Using multivariate analysis, diffuse sclerosing variant was an independent variable for predicting a high risk of persistent and recurrent disease during initial follow-up. However, at a later time, and after further treatment, the disease status was not different between patients with DSPC and those with high-risk cPTC, and only the presence of distant metastases affected the final outcome.nnnCONCLUSIONSnDSPC is a thyroid papillary carcinoma variant characterized by high aggressiveness. In patients with DSPC, the outcome is worse than in patients with low-risk cPTC; and, at presentation, characteristics are somewhat worse than for patients with high-risk cPTC.At medium term, the outcome is similar to that observed in patients with high-risk cPTC, provided aggressive treatment is used (additional surgical intervention, when required, and/or ¹³¹I radiotherapy).

Therapeutic options for elderly diabetic subjects: open label, randomized clinical trial of insulin glargine added to oral antidiabetic drugs versus increased dosage of oral antidiabetic drugs

Glycemic control in elderly persons with typexa02 diabetes mellitus (T2DM) is challenging because they are more likely to have other age-associated medical conditions and to experience hypoglycemia during intensive therapy. A best therapeutic strategy for these patients has not yet been defined. We investigated the efficacy and safety of adding once-daily insulin glargine to patients’ current oral antidiabetic drugs (OAD) regimen, compared to increasing the OAD doses. The study enrolled patients aged 65xa0years or more, with poor glycemic control. Patients were randomized to two groups and entered a 3-week titration period in which their actual therapy was adjusted to meet the study’s glycemic goals, by either adding insulin glargine to current therapy (group A, 27 patients) or increasing current OAD dosages (group B, 28 patients). Thereafter, therapies were continued unchanged for a 24-week observation period. The mean therapeutic dosage of insulin glargine in group A was 14.9xa0IU/day (SDxa0=xa05.0xa0IU/day). During the observation period, mean levels of glycosylated hemoglobin (HbA1c) reduced by 1.5% in groupxa0A and 0.6% in groupxa0B (Pxa0=xa00.381). An HbA1c level <7.0% was achieved by five patients in each group. Mean fasting blood glucose levels reduced by 29 and 15% in groups A and B, respectively (Pxa0=xa00.029). Group A had fewer total hypoglycemic events (23 vs. 79, Pxa0=xa00.030) and fewer patients experiencing any such event (9 vs. 17, Pxa0=xa00.045). Neither a serious hypoglycemic event nor other adverse event occurred. These results suggest that, compared to increasing OAD dosage, the addition of insulin glargine to current OAD therapy is as effective but safer in terms of the risk for hypoglycemia in elderly patients with T2DM.

The diagnostic use of the rhTSH/thyroglobulin test in differentiated thyroid cancer patients with persistent disease and low thyroglobulin levels.

background Serum thyroglobulin (Tg) measurement after TSH stimulation, by either thyroid hormone withdrawal or recombinant human TSH (rhTSH) administration, is the most sensitive method for early detection of patients with persistent or recurrent differentiated thyroid cancer (DTC) after total thyroidectomy and 131I ablation. The use of rhTSH is now increasing because it avoids thyroid hormone suppressive therapy (THST) withdrawal and the consequent symptoms of severe hypothyroidism. Current guidelines suggest measurement of serum Tg 4 days after starting a 2‐day course of rhTSH injections, and assumes that Tg reaches maximum serum levels at that time.