Sebastiano Squatrito

Worldwide increasing incidence of thyroid cancer: update on epidemiology and risk factors.

Background. In the last decades, thyroid cancer incidence has continuously and sharply increased all over the world. This review analyzes the possible reasons of this increase. Summary. Many experts believe that the increased incidence of thyroid cancer is apparent, because of the increased detection of small cancers in the preclinical stage. However, a true increase is also possible, as suggested by the observation that large tumors have also increased and gender differences and birth cohort effects are present. Moreover, thyroid cancer mortality, in spite of earlier diagnosis and better treatment, has not decreased but is rather increasing. Therefore, some environmental carcinogens in the industrialized lifestyle may have specifically affected the thyroid. Among potential carcinogens, the increased exposure to medical radiations is the most likely risk factor. Other factors specific for the thyroid like increased iodine intake and increased prevalence of chronic autoimmune thyroiditis cannot be excluded, while other factors like the increasing prevalence of obesity are not specific for the thyroid. Conclusions. The increased incidence of thyroid cancer is most likely due to a combination of an apparent increase due to more sensitive diagnostic procedures and of a true increase, a possible consequence of increased population exposure to radiation and to other still unrecognized carcinogens.

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.

Insulin/IGF-I hybrid receptors play a major role in IGF-I signaling in thyroid cancer.

The insulin-like growth factor-I (IGF-I) plays an important role in determining the biological behavior of a variety of malignancies. We measured IGF-I, its receptor and related receptors in thyroid cancer. IGF-I was present both in normal thyroid tissue and in thyroid cancer tissue and it was produced by stromal cells but not by thyrocytes. Values were significantly higher in malignant than in normal tissue. IGF-I receptors (IGF-I-Rs) and the homologous insulin receptors (IRs) were found overexpressed in both thyroid cancer cell lines (n = 4) and specimens (n = 17) as compared to normal values. In addition, high levels of hybrid IGF-I/insulin receptors (IR/IGF-I-Rs) were present in both thyroid cancer specimens and cell lines. IR/IGF-I-R hybrids were the most represented type of receptor in 14/17 specimens and exceeded the IGF-I-R content in all cases. Hybrid content correlated with the IR and IGF-I-R content, suggesting that in thyroid tissue hybrid formation occurs by random assembly of IR and IGF-I-R half receptors. Hybrid receptor autophosphorylation was stimulated by IGF-I with high affinity. In cells with a high IR/IGF-I-Rs content, blocking antibodies specific to these receptors substantially inhibited IGF-I induced cell growth. These data indicate that the IGF-I system is overactivated in thyroid cancer and that IR/IGF-I-R hybrid receptors play an important role in IGF-I mitogenic signaling in these tumors.

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.

Maternal hypothyroxinaemia during the first half of gestation in an iodine deficient area with endemic cretinism and related disorders

OBJECTIVE Iodine deficiency is well known as the cause of several disorders such as endemic goitre and cretinism, along with a wide spectrum of psychoneurological development disorders including endemic mental deficiency and endemic cognitive deficiency, which are generally correlated to damage to the fetus. Such damage Is, by Inference, deemed a consequence either directly of iodine deficiency or of insufficient availability of thyroxine at the feto‐placental unit level. Early pregnancy represents the crucial period for neurogenesis in the embryo. Several experimental studies have emphasized the direct role of maternal T4 in neurological embryo‐genesis, before the onset of fetal thyroid function and, therefore, Its protective role In fetal thyroid failure. The objective of this study was to evaluate whether Iodine deficiency may Influence thyroid status of pregnant women throughout the first half of pregnancy.

Papillary Thyroid Microcarcinomas: A Comparative Study of the Characteristics and Risk Factors at Presentation in Two Cancer Registries

CONTEXT Papillary thyroid microcarcinoma (PTMC) is an indolent neoplasia, often asymptomatic and discovered incidentally. Some PTMCs, however, exhibit a more aggressive behavior, frequently recur, and can even cause cancer-related death. OBJECTIVE The aim of this study was to evaluate the prevalence of PTMCs and the associated risk factors at presentation in 2 thyroid cancer registries from areas with different genetic and environmental characteristics. DESIGN AND PATIENTS We conducted a retrospective, observational study of all incident cases of PTMCs recorded over a 5-year period in the Sicilian Regional Registry for Thyroid Cancer (SRRTC) and in the Surveillance Epidemiology and End Results (SEER) US registry. SETTING The study took place at an academic hospital. RESULTS The incidence of PTMCs was much higher in Sicily (1777 PTMC diagnosed in 2002-2006; age-standardized incidence rate for the world population [ASRw] = 5.8 per 100 000) than in the United States (14 423 PTMC in the period 2004-2008; ASRw = 2.9 per 100 000). Within the SRRTC, a significantly higher incidence was observed in the volcanic area (ASRw = 10.4 vs 4.6 in the rest of Sicily). In Sicily, the female to male ratio was higher, and PTMC patients were younger. In both registries, a significant inverse correlation was observed between age and tumor size. Young patients (≤45 y) exhibited a higher frequency of nodal metastases. CONCLUSIONS PTMC incidence is twice as high in Sicily compared with the United States, and within Sicily, the incidence is twice as high in the volcanic area. In young patients, PTMCs are larger at presentation and exhibit more risk factors. In both registries, more than 35% of PTMCs exhibited 2 or more risk factors, suggesting that they may require surgery and follow-up similar to that of larger carcinomas.

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.

Clinical and molecular mechanisms favoring cancer initiation and progression in diabetic patients

Cancer incidence and mortality are higher among diabetic patients. This review examines the mechanisms, both general and site-specific, for this increase. Hyperglycemia and hyperinsulinemia, which are the major abnormalities that characterize diabetes, can promote cancer via both independent and synergic mechanisms. Insulin is both a metabolic hormone and a growth factor that promotes cell proliferation. When insulin levels are increased due to either insulin resistance or insulin treatment, their mitogenic effect is more marked in malignant cells that frequently overexpress the insulin receptor and, more specifically, its A isoform that has predominant mitogenic activity. Hyperglycemia provides energy for malignant cell proliferation and, via the peculiar energy utilization of cancer cells, favors cancer growth and neoangiogenesis. Additionally, diabetes-associated obesity has cancer-promoting effects due to mechanisms that are specific to excess fat cells (such as increased peripheral estrogens, increased pro-mitogen cytokines and growth factors). Also fat-associated chronic inflammation can favor cancer via the cell damage caused by reactive oxygen species (ROS) and via the production of inflammatory cytokines and transcription factors that stimulate cancer growth and invasiveness. Finally, the multiple drugs involved in the treatment of diabetes can also play a role. Diabetes-associated comorbidities, tissue-specific inflammation, and organ-specific dysfunctions can explain why the risk of cancer can differ by tissue type among diabetic patients. The increased risk of cancer-related mortality is moderate among individual patients with diabetes (RR = 1.25), but the pandemic nature of the disease means that a considerable number of lives could be spared through a better understanding of the factors associating diabetes and cancer.

Insulin and its analogs: actions via insulin and IGF receptors

Insulin analogs are artificially modified insulin molecules that allow better metabolic controls of diabetes through either more rapid or more prolonged activity. The interaction of insulin analogs with the insulin receptor isoforms (IR-A and IR-B) and with the IGF-I receptor (IGF-IR) is similar but not identical to that of insulin, and therefore, their biological effects do not always reproduce insulin actions in terms of quantity, quality and timing. Studies on in vitro models indicate that short-acting analogs elicit molecular and biological effects that are similar, but not identical, to those of insulin via IR-A, IR-B and IGF-IR. In contrast, long-acting analogs behave in a more different way relative to insulin. Although data are not homogeneous and observations on the more recently introduced detemir are scarce, both glargine and detemir often show a decreased binding to IR and increased binding to IGF-IR. Also, intracellular signaling is different with respect to insulin, with a prevalent activation of the ERK rather than the AKT pathway. Finally, an increased mitogenic response has often been observed with these analogs in a variety of cell models. Of course, in vitro studies do not necessarily reflect what occurs in patients, due to the different metabolism of analogs in vivo and their interaction with components of the extracellular environment. After many years of analog’s use, observations in patients indicate that insulin analogs are both effective and safe. Prospective clinical studies, however, may add further useful information on the issue of the insulin analogs’ possible differences with respect to native insulin.

Comparison of Combined Therapies in Treatment of Secondary Failure to Glyburide

Objective To compare the effectiveness of alternative combined treatments in patients with non-insulin-dependent diabetes mellitus (NIDDM) with secondary failure to sulfonylureas. Research Design and Methods A crossover study was carried out by randomly assigning 16 NIDDM patients to a combined treatment with the addition of either a single low-dose bedtime injection of 0.2 U/kg body wt NPH insulin or an oral three times a day administration of 1.5 g/day metformin to the previously ineffective glyburide treatment. Results Both combined therapies significantly (P <0.01) reduced fasting plasma glucose (FPG), postprandial plasma glucose (PPPG) and percentage of HbA1. The addition of metformin was more effective than the addition of insulin (P <0.01) in improving PPPG in the 8 patients with higher post-glucagon C-peptide levels. In contrast, the efficacy of neither combined therapy was related to patient age, age of diabetes onset, duration of the disease, percentage of ideal body weight, and FPG. The addition of insulin but not metformin caused a significant (P <0.01) increase of mean body weight. Neither combined treatment caused changes in serum cholesterol and triglyceride levels. No symptomatic hypoglycemic episode was reported in any of the 16 patients. CONCLUSIONS The addition of bedtime NPH insulin or metformin was effective in improving the glycemic control in most NIDDM patients with secondary failure to glyburide. The combination of metformin and sulfonylurea was more effective in reducing PPPG and did not induce any increase of body weight.