Well differentiated thyroid carcinoma: new perspectives and old dilemmas

The diagnosis of well differentiated carcinoma (i.e papillary carcinoma and follicular carcinoma) represents one of the most challenging issue in thyroid pathology. Aim of the present review is to discuss new perspective and old problems in this topic. Three main subjects are developed, corresponding to: 1) the role of fine needle aspiration versus frozen section examination in pre- or peri- operative diagnosis; 2) the management of small papillary tumour; 3) pathological classification of those tumours indeterminate for papillary or follicular nature. There is general agreement that fine needle aspiration represent the best pre-operative diagnostic tool for thyroid nodules; foremost limits are represented by "not diagnostic" and 'follicular lesion, NOS". The former should be repeated or, if suspicious for papillary lesion, improved with intra-operative apposition cytology; the latter should be deferred to histology with frozen section evaluation reserved to those institution with daily practice on this issue. The management of papillary micro-carcinoma (i.e. papillary carcinoma smaller than 1 cm.) in the setting of an otherwise benign thyroid disease is a matter of debate, since several clinicians suggest to consider these as incidental findings thus avoiding additional treatment. Recently this attitude has been supported by the proposal to regard these lesion as "tumour" and not carcinoma: available data on follow up seems to sustain and favour this approach. There exist a group of well differentiated tumours of the thyroid lacking the criteria to be diagnosed either as papillary (i.e. nuclear grooves, nuclear pseudo-inclusion and nuclear clearing) or follicular (i.e. capsular or vascular invasion) carcinoma; for these lesion, whose behaviour (nodal or blood metastasis) can not be predicted, it has been suggested the term of well differentiated tumour of uncertain malignant potential. Finally it has to be mentioned the possible role of molecular biology in the diagnosis of well differentiated thyroid carcinoma; indeed markers such as RET/PTC or PAX8/PPARgamma, which to date have been employed mainly in basic research, might represent useful diagnostic (and therapeutic) tools in the future.     

Oral antihyperglycemic agents and renal disease: new agents, new concepts

The results of the Diabetes Control and Complications Trial (DCCT) and UK Prospective Diabetes Study trials in type 1 and type 2 diabetes, respectively, have proved the importance of intensive glucose management in the prevention of microvascular complications (retinopathy, nephropathy, and neuropathy). Both trials showed encouraging trends for a decrease in macrovascular complications, and this is being pursued in new studies. These findings have led to more strict goals for glucose control. As glucose levels are aimed to be closer to the normal range, the risk for hypoglycemia also increases dramatically. The choice of the agent therefore is more influenced currently by the risk for hypoglycemia. There are presently four classes of oral antihyperglycemic agents. These agents differ greatly in terms of mechanisms of action, efficacy, side effect profiles, and cost. Except for Acarbose, all classes decrease the glycosylated hemoglobin by a similar magnitude: 1.0 to 1.5%. In chronic renal failure, the oral agents that can be used therefore include the insulin secretagogues repaglinide and nateglinide and the thiazolidinediones (rosiglitazone and pioglitazone) with caution. Insulin also can be used safely in renal failure.     

Protein therapies and antiproliferatives: a new paradigm in immunosuppression

The development of immunosuppressive therapies has focused on inhibiting effects of the activated T cell. The introduction of powerful immunosuppressive agents that interrupt the effects of T-cell activation, such as the calcineurin inhibitors (CNIs), has revolutionized solid organ transplantation. However, the ubiquitous location of their targets causes a number of side effects, which can compromise recipient health and long-term allograft survival. Therefore, a common goal in the development of emerging immunosuppressive strategies is to maintain efficacy and minimize toxicities related to these immunosuppressant compounds. The rationale for CNI-free regimens that exploit combinations of antiproliferative and protein therapeutic agents is attractive. Recently, studies employing these agents in CNI-free regimens have begun to offer additional insight into both the potential benefits and limitations of currently available strategies. The currently available biologic agents provide either too potent immunosuppression (eg, T-cell depletion) or inhibit an aspect of T-cell activation too limited to provide adequate rejection prophylaxis (eg, interleukin 2 receptor [IL-2R] blockade). Growing evidence suggests that costimulation blockade, particularly those protein therapeutics targeting CD28 and CD40, provides the correct balance between immunosuppressive and low toxicity, with a more specific, nondepleting, and timely targeting of the immune response. Already, results from a phase 2 trial suggests that combination with a costimulation blockade using belatacept with mycophenolate mofetil as a maintenance therapy after induction with an IL-2R blocker is closest to fulfill this promise. Belatacept represents an emerging immunosuppression paradigm with maintenance protein therapy that fulfills the need of more selective immunosuppression with reduced toxicities, which offers the potential of improving long-term outcomes in renal transplant.     

Ethical dilemmas. The new is old

There are no predictable external cues to ethical dilemmas, therefore, physicians must develop internal sensitivity to these issues. Because there is only a finite number of ethical problems, these recur with predictable frequency. The current essay reviews three books from the literature that present ethical difficulties that were unrecognized until the consequences were obvious. By considering these, and their parallels today, present physicians may avoid the ethical mistakes of their predecessors.     

Hereditary polyposis syndromes remain a challenging disease entity: Old dilemmas and new insights

In this editorial we present an overview and insights of the management of hereditary polyposis syndromes. The primary focus was on familial adenomatous polyposis, juvenile polyposis syndrome and Peutz-Jegher syndrome. Genetic testing has become increasingly available and is easier than ever to integrate into clinical practice. Furthermore, several genes have been added to the expanding list of genes associated with hereditary polyposis syndromes, allowing for precise diagnostics and tailored fo...     

Clinical trials,immunosuppression and renal transplantation: new trends in design and analysis

Clinical trials provide a framework to search for more effective and less toxic immunosuppressive agents to control renal transplant rejection. Some methodological aspects are presented. Patient selection and the choice of study endpoints are discussed with emphasis on standardized definitions and classification of histopathology, and on qualification and quantification of chronic rejection. Choosing a Bayesian or a frequentist approach and the afferent hypotheses is discussed together with the interpretation of a P-value and a confidence interval. Strategies for limiting the number of patients, increasing power and feasibility are reviewed, including discussion of surrogate endpoints. New approaches to statistical analysis are then presented, including intention-to-treat versus per-protocol analysis, analysis of correlated data, dependent censoring, and meta-analysis applied to renal transplantation. Pharmacoeconomics are finally introduced as necessary for implementation of decision making regarding therapeutic strategies. Reporting research increases its standards, and the CONSORT (Consolidated Standards of Reporting Trials) and QOROM (Quality of Reporting of Meta-analyses) criteria are to be integrated in the process of clinical trial procedures. In conclusion, observational studies are presented as part of an evidence-based approach in the hierarchy of evidence, keeping in mind that high quality, randomized, controlled trials are still necessary to decrease uncertainty in the field of renal transplantation.     

Maintenance immunosuppression with mycophenolate mofetil and corticosteroids in pediatric kidney transplantation: temporary benefit but not without risk

BACKGROUND: Aiming at reducing cyclosporine toxicity, we investigated safety and efficacy of mycophenolate mofetil (MMF) as an immunosuppressive drug in pediatric kidney transplantation compared with cyclosporine (CsA), both in combination with corticosteroids. METHODS: One year after kidney transplantation, children on triple immunosuppression, having experienced no more than one, steroid-sensitive, acute rejection episode, were randomized to withdrawal of either CsA or MMF and were followed for 2 yr. RESULTS: In each group, two patients had an acute rejection episode during withdrawal. Treatment failure occurred in 3 of 21 MMF and 5 of 23 CsA patients. Final analysis was for 18 patients in either group. A larger than 10 mL/min 1.73 m decrease in glomerular filtration rate was observed in more patients on CsA than on MMF (73% vs. 29%, P=0.019). No differences in blood pressure or nightly decrease of blood pressure were noted. Hypercholesterolism improved in the MMF (-16%), but not the CsA group (+5%, P<0.05), over the first, but not over both study years. Differences in triglycerid levels between groups were not shown. At study end, MMF patients tended to have lower hemoglobin levels than patients on CsA. Two MMF patients experienced a first acute rejection episode during the second study year, resulting in chronic transplant glomerulopathy with graft loss in one and deterioration of kidney function in the other. CONCLUSION: In pediatric kidney transplantation, maintenance immunosuppression with MMF together with corticosteroids has short-term benefits for kidney function and lipid pattern compared with CsA but is not without risk of complications.     

Myocardial infarction: Role of new antiplatelet agents

Thienopyridines have become the cornerstone of treatment of percutaneous coronary intervention although no survival benefit has ever been shown with clopidogrel despite increasing loading doses. Newly developed P2Y(12)?inhibitors are more potent, more predictable and have a faster onset of action than clopidogrel, characteristics that make them particularly attractive for high-risk PCI. Four new P2Y(12)?inhibitors have been tested each of them having particular individual properties. Prasugrel is an oral prodrug leading to irreversible blockade of the P2Y(12)?receptor and is approved worldwide for ACS PCI. Ticagrelor is a direct-acting and reversible inhibitor of the P2Y(12)?receptor with potentially more pleiotropic effects. Cangrelor is an intravenous direct and reversible inhibitor of the P2Y(12)?receptor providing the highest level of inhibition and elinogrel is an intravenous and oral P2Y(12)?antagonist with a direct and reversible action. Both prasugrel and ticagrelor, opposed to clopidogrel, have shown that stronger P2Y(12)?inhibition led respectively to significant 19?% and 16?% relative risk reduction of a similar primary endpoint combining cardiovascular death, nonfatal myocardial infarction, or nonfatal stroke. Both drugs showed a significant 0.6?% absolute excess of TIMI major bleeding not related to CABG surgery. The effect of these new compounds is prompt, predictable and powerful as compared to clopidogrel. Their net benefit is particularly marked in PCI for STEMI patients, in which there is no significant increase in major bleeding when compared with clopidogrel. However, because in clinical trials patients perceived to be at higher risk for bleeding usually are excluded, the risk of major and even fatal bleeding might even be higher in a "real-world" setting i.e. in the elderly patient with comorbidities.     

The new antithrombotic agents

Current antithrombotic agents include anticoagulants (unfractionated and low-molecular-weight heparin, and antivitamin K) and platelet aggregation inhibitors (aspirin, ticlopidine, clopidogrel). Two areas are under particular investigation: specific inhibition, direct or indirect, of factor Xa and factor IIa. Pentasaccharide, an indirect anti-Xa, has proved effective in curing deep-vein thrombosis and more effective than enoxaparin for prophylactic treatment after orthopedic surgery. Administered in a single subcutaneous injection daily, it has no risk of thrombocytopenia; laboratory surveillance is based on anti-Xa activity. Hirudin and melagatran act by direct thrombin inhibition. Unlike hirudin (which requires monitoring of active coagulation time or ecarin clotting time), melagatran requires no laboratory monitoring. It is not associated with an increased risk of hemorrhage. But there is no true antidote at this time. If its efficacy is confirmed, ximelagatran, the orally active prodrug of melagatran, may facilitate the long-term treatment now reserved for antivitamin K. Three antagonists of the tissue factor-factor VIIa complex are also under development: rNAPc2 (Recombinant Nematode Anticoagulant Protein C2), ASIS (Active Site Inhibitor Factor Seven) and recombinant TFPI (Tissue Factor Pathway Inhibitor). Antiplatelet drugs are the reference antithrombotic agents for the prevention and treatment of arterial thrombosis. Aspirin remains in first place (75 to 300 mg/d) but the modest superiority of the thienopyridines (clopidogrel and ticlopidine) is established. Hemogram monitoring is no longer necessary for clopidogrel. Use of aspirin + a thienopyridine after placement of a coronary stent has been validated. Laboratory monitoring of antiplatelet treatments has not been codified.