Down-regulation of TDT transcription in CD4(+)CD8(+) thymocytes by Ikaros proteins in direct competition with an Ets activator.

Ikaros is a unique regulator of lymphopoiesis that associates with pericentromeric heterochromatin and has been implicated in heritable gene inactivation. Binding and competition experiments demonstrate that Ikaros dimers compete with an Ets activator for occupancy of the lymphocyte-specific TdT promoter. Mutations that selectively disrupt Ikaros binding to an integrated TdT promoter had no effect on promoter function in a CD4(+)CD8(+) thymocyte line. However, these mutations abolished down-regulation on differentiation, providing evidence that Ikaros plays a direct role in repression. Reduced access to restriction enzyme cleavage suggested that chromatin alterations accompany down-regulation. The Ikaros-dependent down-regulation event and the observed chromatin alterations appear to precede pericentromeric repositioning. Current models propose that the functions of Ikaros should be disrupted by a small isoform that retains the dimerization domain and lacks the DNA-binding domain. Surprisingly, in the CD4(+)CD8(+) thymocyte line, overexpression of a small Ikaros isoform had no effect on differentiation or on the pericentromeric targeting and DNA-binding properties of Ikaros. Rather, the small isoform assembled into multimeric complexes with DNA-bound Ikaros at the pericentromeric foci. The capacity for in vivo multimer formation suggests that interactions between Ikaros dimers bound to the TdT promoter and those bound to pericentromeric repeat sequences may contribute to the pericentromeric repositioning of the inactive gene.     

Clinical-molecular factors predicting response and survival for tyrosine-kinase inhibitors

The development of drugs with special mechanisms of action, such as tyrosine kinase inhibitors (TKIs), means that new clinical-molecular questions are being examined and this will help us to better select from the treatments available. In this study we review questions of survival and response to TKIs, attempting to distinguish prediction-and prognosis-related factors, at both the clinical and molecular levels. The evidence available today allows us to affirm that the benefits of TKI treatment occur regardless of the patient’s status as a smoker, his/her gender or histological sub-type. Interestingly, in a subset analysis of ever-smokers, men with squamous cell histology derived a statistically significant survival benefit from erlotinib, a population that was previously thought not to benefit. The question of who should receive TKIs is still not completely resolved. Therefore, there should be an international effort to achieve a prognostic index, as has been done for lymphomas, that combines molecular and clinical factors. Such an index would classify patients into several sub-groups, defining the likelihood of non-response to TKIs. Supported by an unrestricted educational grant from Pfizer     

Reticular telangiectatic erythema associated with an implantable cardioverter defibrillator

Reticular telangiectatic erythema (RTE) is a skin reaction associated with implantable cardiac devices (ie, pacemakers and cardioverter defibrillators). We present a patient who developed an erythematous patch over the implantable cardioverter defibrillator site. We discuss the clinical features, histologic findings, and patch testing of this entity.     

SEOM clinical guidelines for the treatment of thyroid cancer

Although thyroid cancer represents less than 1% of malignant tumours, its increased incidence detected in recent years and the appearance and development of new drugs targeting specific molecular targets has attracted the attention of the doctors involved in this pathology, especially medical oncologists. For this reason it is important at this critical point, when treatment may be substantially changed, to establish and agree updated guidelines. These guidelines should incorporate the newly developed strategies that, although still preliminary in evidence level, will surely have an important role, especially in relapsed and refractory tumours, which are unsuitable for surgical or radio-iodine treatment. Particular histological and molecular features of these tumours must be taken into account in order to optimise therapeutic approaches.     

SEOM clinical guidelines for the treatment of anal cancer

Anal carcinoma is an uncommon disorder accounting for less than 2% of large bowel malignancies and 1–6% of anorectal tumours. Its incidence ranges between 0.5 and 1% per 100,000. Local staging should be done with MR imaging using an external pelvic phased-array coil. Treatment strategy should be optimally discussed in a multidisciplinary team. HIV-positive patients seem to achieve similar response rate and overall survival to HIV-negative patients but with increased toxicity and higher local recurrences. Combined modality treatment with irradiation and chemotherapy has resulted in complete response over 90% and local control over 85%. This guide gives recommendations for diagnosis, staging and treatment.