Carles Zafon

Iron in obesity. An ancient micronutrient for a modern disease.

Iron is a necessary constituent of several macromolecules involved in cell metabolism, but, at the same time, it could be a potentially dangerous element. For this reason iron balance must be finely regulated. At present, obesity has been recognized as a worldwide public health problem. Excess body fat is associated with increased all‐cause mortality and increased risk for several medical morbidities. Many studies have shown that obesity might increase the risk of iron deficiency but, at the same time, obese subjects exhibit high serum ferritin levels. Recent studies seem to indicate that obesity is associated with iron deficiency although the aetiology appears to be multifactorial and includes (i) A decrease in iron food intake; (ii) An impairment of intestinal iron uptake and iron release from stores because of an overexpression of hepcidin and (iii) Inadequate iron bioavailability because of inflammation. In addition, abnormal ferritin concentrations can be explained by chronic inflammation rather than by iron overload. The aim of the present article is to review current knowledge of iron and obesity.

Thyroid cancer: molecular aspects and new therapeutic strategies.

Despite that thyroid cancer accounts for over 90% of tumors that arise from the endocrine system, these tumors barely represent 2% of solid tumors in adults. Many entities are grouped under the general term of thyroid cancer, and they differ in histological features as well as molecular and clinical behavior. Thus, the prognosis for patients with thyroid cancer ranges from a survival rate of >97% at 5 years, in the case of differentiated thyroid tumors sensitive to radioactive iodine, to a 4-month median survival for anaplastic tumors. The high vascularity in these tumors and the important role that oncogenic mutations may have in the RAS/RAF/MEK pathway and oncogenicity (as suggested by activating mutations and rearrangements of the RET gene) have led to the development of multitarget inhibitors in different histological subgroups of patients. The correct molecular characterization of patients with thyroid cancer is thought to be a key aspect for the future clinical management of these patients.

Preoperative Thyrotropin Serum Concentrations Gradually Increase from Benign Thyroid Nodules to Papillary Thyroid Microcarcinomas Then to Papillary Thyroid Cancers of Larger Size

We evaluated the preoperative serum thyrotropin (TSH) levels in 386 patients operated on for nodular thyroid disease (NTD). TSH levels for cases with final benign disease and differentiated thyroid carcinoma (DTC) were compared. No evidence of cancer was detected in 310 patients (80.3%), whereas malignancy was present in 76 cases (19.7%). Mean TSH concentration was 1.36 ± 1.62 mU/L in benign patients and 2.08 ± 2.1 in cases with malignant lesions (P = 0.0013). The group of malignancy was subdivided in papillary thyroid carcinoma (PTMC) versus thyroid cancer of larger size (TCLS). Mean TSH was 1.71 ± 1.52 in PTMC and 2.42 ± 2.5 in TCLS. Significant differences were found when all groups (benign, PTMC and TCLS) were compared (P < 0.001). However, pairwise comparisons between them showed that differences were only significant between benign and TCLS groups (P < 0.01). In conclusion, TSH levels were higher in patients with a final diagnosis of DTC. Moreover, it appears that there exists an increment in tumor size as a function of increment in the TSH level.

Vía de señalización dependiente de la proteincinasa de activación mitogénica en el carcinoma papilar de tiroides. De las bases moleculares a la práctica clínica

In recent years, significant progress has been made in elucidating the genetic bases promoting tumorigenesis in various human neoplasms. Constitutive activation of the mitogen-activated protein kinase (MAPK) signaling pathway is a major event in the carcinogenesis of papillary thyroid carcinoma (PTC), the most prevalent endocrine malignancy. Affected elements include RET/PTC rearrangements and point mutations of the Ras and BRAF genes. Mutations in these genes are found in over 70% of PTC. Chromosomal RET rearrangements, called RET/PTC, result in constitutive ligand-independent activation of RET kinase, which was the first genetic anomaly detected in PTC and is found in 5-70% of tumoral samples. Although less frequent, the activation of other tyrosine kinase receptors, such as NTRK1, c-Met or EGFR, has also been reported in PTC. The BRAF mutation represents the most common genetic alteration found in PTC. More than 90% of BRAF mutations lead to a change of a valine to a glutamic acid at position 600 (V600E). Finally, Ras is the least affected molecule in the pathway. A relationship between clinical behavior and these genetic alterations has been proposed. Thus, the BRAF mutation is associated with a more aggressive PTC phenotype and is correlated with poorer outcomes. However, no clear association has been found between RET/PTC and clinical features. The discovery of these alterations opens the way to new therapeutic strategies, especially to treat those patients in whom conventional therapy is not effective. Several new drugs are being tested, such as small molecule tyrosine kinase inhibitors. Some of these recently developed agents have begun to be used with promising results.En los ultimos anos se ha empezado a descubrir las bases geneticas de la carcinogenesis en diferentes neoplasias humanas. La desregulacion de la via de senalizacion dependiente de la proteincinasa de activacion mitogenica (MAPK) es un mecanismo fundamental en la oncogenesis del carcinoma papilar de tiroides (CPT), el tumor endocrino mas frecuente. Concretamente, tres integrantes de la via –el receptor tirosincinasa RET, Ras y BRAF– se encuentran implicados en mas del 70% de los casos. El reordenamiento cromosomico de RET, denominado RET/PTC, ocasiona la activacion enzimatica de esta tirosincinasa. Fue la primera alteracion genetica especifica del CPT y se encuentra en un 5-70% de las muestras tumorales. En menor proporcion se han encontrado activaciones constitutivas de otros receptores tirosincinasa, como NTRK1, c-met o EGFR. La mutacion de BRAF es la alteracion genetica mas frecuente en el CPT. En la mayoria de los casos, la mutacion ocasiona un cambio de valina por acido glutamico en la posicion 600 (V600E). Finalmente, Ras es la molecula menos afectada de la via. La presencia de estas alteraciones se correlaciona, en algunos casos, con el comportamiento clinico de la enfermedad. Asi, la mutacion de BRAF condiciona una mayor agresividad y un peor pronostico. No hay tanto consenso en el papel de RET/PTC. Por otro lado, el descubrimiento de estas alteraciones abre la puerta a nuevas estrategias terapeuticas, en especial para los pacientes en quienes el tratamiento convencional resulta inefectivo. Entre las nuevas opciones se encuentran los inhibidores de las tirosincinasas. Algunos farmacos de esta familia han empezado a ser utilizados con resultados esperanzadores.

Clinical significance of RET/PTC and p53 protein expression in sporadic papillary thyroid carcinoma

Aims:  Rearranged during Transfection (RET)/papillary thyroid carcinoma (PTC) and p53 are two genes involved in the pathogenesis of PTC. It has been suggested that RET/PTC expression is associated with higher rates of local extension and lymph node involvement, whereas p53 mutations are more frequent in poorly differentiated and anaplastic carcinomas. In addition, experimental studies have shown that p53 activity can modify the behaviour of PTC carrying RET/PTC. The aim of this study was to investigate the expression of both RET/PTC and p53 in order to evaluate their usefulness as prognostic factors.

Differences in the Form of Presentation between Papillary Microcarcinomas and Papillary Carcinomas of Larger Size

Papillary thyroid carcinomas (PTCs) with a diameter ≤1 cm are referred to as papillary microcarcinomas (PTMCs). The prognostic factors for PTMCs have not been defined. Different clinical and histopathologic variables were studied in 152 PTCs, including 74 PTMCs and 78 PTCs of larger size. We found that PTMCs are associated with less multifocality (P = .046) and bilaterality (P = .003), fewer lymphadenectomies (P < .001), and a higher rate of incidental tumours (P < .001). Moreover, patients with a low aggressive profile were significantly older than the remaining patients (54 ± 13.7 years versus 45.8 ± 13.1 years; P = .001). In conclusion PTMCs show significant differences compared to PTCs of larger size in the form of presentation. Furthermore, it is possible that the classic risk factors, which are well validated in PTCs, such as age, must be cautiously interpreted in the current increasing subgroup of PTMCs.

Variables Involved in the Discordance between HbA1c and Fructosamine: The Glycation Gap Revisited

Aims Glycation gap (GG) is defined as the difference between the measured level of HbA1c and the level that would be predicted from its regression on the fructosamine level. The aims of the study were: 1) To determine the reproducibility and consistency of GC; 2) To discover factors related to GG value. Given that metformin might increase glucose transport through the erythrocyte membrane, this treatment was also considered in the analyses of the results. Methods GG was calculated in two blood samples separated 30.6 (SD 7.3) weeks, obtained in 508 type 2 diabetic patients. The following variables were considered: HbA1c, fructosamine, glucose, creatinine, hematological parameters and treatment with metformin. Multivariate and logistic regression analyses were performed to explore the variables independently related to CG. Results GG was reproducible and consistent over time. Creatinine, mean corpuscular hemoglobin concentration (MCHC), and glycemia (inverse relationship); and HbA1c and treatment with metformin (direct relationship) were independently related to GG. Patients treated with metformin showed higher HbA1c values, despite similar fructosamine concentrations, than patients not treated with the drug. Conclusions GG is independently related to serum levels of creatinine, MCHC and treatment with metformin. The spurious effect of metformin on Hb glycation could have serious clinical implications and should be considered when interpreting the results of clinical trials.

Expression of p21cip1, p27kip1, and p16INk4a Cyclin-Dependent Kinase Inhibitors in Papillary Thyroid Carcinoma: Correlation with Clinicopathological Factors

In a variety of human malignancies, aberrant expression of proteins involved in the control of cell-cycle progression has been reported. In this study, p21cip1, p27kip1, and p16INk4a cyclin-dependent kinase inhibitors were analyzed to evaluate their usefulness in clinical management of papillary thyroid carcinoma (PTC). Archived material derived from 46 cases of PTC was analyzed immunohistochemically. Protein expression was ascertained on tissue microarrays, and results were correlated with clinicopathological features of the patients. Positive immunostaining was observed in 14 (30,4%) p21cip1, 26 (56,5%) p27kip1, and 14 (30,4%) p16INk4a cases. No significant correlation between p21cip1 or p27kip1 and clinical factors was found. In contrast, p16INk4a expression showed a significant correlation with initial extension of the disease. Therefore, 45.8% of patients with loco-regional extension were p16INk4a positive, whereas overexpression was only seen in 15.7% of cases with intrathyroid disease (p < 0.05). Moreover, all patients with simultaneous p16INk4a positivity and lack of p27kip1 staining (four patients) presented lymph node metastases. In contrast, only 12 (28.5%) of the remaining patients showed lymph node tumor involvement. In conclusion, p16INk4a expression suggests extrathyroid neck extension of PTC. This effect is enhanced when p27kip1 is negative. We think that their analysis by immunohistochemistry could be useful in the management of patients with PTC.

Preoperative TSH level and risk of thyroid cancer in patients with nodular thyroid disease: nodule size contribution ☆

BACKGROUND Many reports have supported the relationship between high preoperative TSH levels and risk of thyroid cancer in nodular thyroid disease (NTD). OBJECTIVES We investigated whether TSH levels are related to the risk of differentiated thyroid carcinoma (DTC) in patients who have undergone total thyroidectomy for NTD. The relationship between TSH and size of malignant nodule was investigated. Finally, we assessed whether TSH levels are related to DTC and presence of additional benign nodules. PATIENTS AND METHODS A retrospective study of 980 patients was conducted. Variables included age at diagnosis, TSH level, nodule size, gender, final histology (benign versus DTC), and type of malignancy. RESULTS Malignancy was present in 261 (26.6%) patients. These patients had higher median TSH levels as compared to those with no malignancy (1.61 mU/L (0.9-2.5) versus 0.9 mU/L (0.3-1.6); p-value<0.001). TSH was higher in patients with DTC in whom the largest nodule was malignant than in patients in whom the largest nodule was benign (1.80 mU/L (1.1-2.6) versus 1.38 mU/L (0.7-2.1) respectively; p-value=0.025). A significant correlation was seen between malignant nodule size and TSH level, but not between TSH levels and size of the largest benign nodule. CONCLUSIONS Our study supported an association between preoperative TSH levels and risk of DTC in patients with NTD. There was also a direct relationship between malignant nodule size and TSH levels. By contrast, no relationship was found between the size of benign nodules and TSH levels.

Immunohistochemical Expression of Estrogen Receptor-α and Progesterone Receptor in Patients with Papillary Thyroid Cancer

Background: Papillary thyroid cancer (PTC) prevalence is nearly 3 times higher in females than in males. This gender difference suggests that growth and progression of PTC might be influenced by female sex hormones. Objectives: To analyze the expression of both estrogen receptor (ER)-α and progesterone receptor (PR) by immunohistochemistry in 203 PTC patients. Methods: ER-α and PR expression was evaluated in paraffin-embedded tumor tissue samples of 45 males and 158 females followed up for 7.2 ± 3.7 years. Results: ER-α was expressed in 52 (25.6%) patients (41 females and 11 males) and PR in 94 (46.3%) patients (75 females and 19 males). ER-α and PR were coexpressed in 31 (15.3%) patients (27 females and 4 males). ER-α expression correlated significantly with tumor size in the whole sample (ER-α positive 22.8 ± 11.8 mm vs. ER-α negative 15.1 ± 12.4 mm; p = 0.02) and in the subgroup of women (ER-α positive 18.8 ± 12.8 mm vs. ER-α negative 14.9 ± 12.3 mm; p = 0.048). In addition, ER-α expression significantly correlated with remission of the disease. In fact, of the 192 patients followed up, 50/153 (32.7%) disease-free patients were ER-α positive, in contrast to only 3/39 (7.7%) with evidence of disease persistence/recurrence (χ2 = 8.5, p = 0.0036). PR expression was not associated with any of the parameters analyzed. Conclusions: The present study confirmed recent data indicating that ER-α and PR expression is a common finding in thyroid tumor tissue. However, in contrast to previous reports, we observed an association between ER-α expression and a more favorable outcome in PTC patients.