Cricotracheal resection for laryngeal invasion by thyroid carcinoma: our experience.

Invasion of the laryngeal framework by thyroid carcinoma requires specific surgical techniques and carries a higher rate of complications that deserve to be highlighted. We reviewed our data from 1995 to 2012 and found six patients with laryngotracheal invasion by thyroid carcinoma. All underwent total thyroidectomy and single-stage cricotracheal resection, plus anterolateral neck dissection. Three had airway obstruction that necessitated prior endoscopic debulking. None of the patients needed a tracheotomy. There were four cases of papillary carcinoma, and two cases of undifferentiated carcinoma. One patient died of complications of the procedure (anastomotic dehiscence and tracheo-innominate artery fistula). Another died 2 months after the procedure from local recurrence and aspiration pneumonia. One case presented recurrence at 15 months, which was managed by re-excision and adjuvant radiotherapy; after 26 months of follow-up, he has no evidence of locoregional recurrence. The three other patients are alive without evidence of disease at 6, 18 and 41 months, respectively. Cricotracheal resection for subglottic invasion by thyroid carcinoma is an effective procedure, but carries significant risks of complications. This could be attributed to the devascularisation of the tracheal wall due to the simultaneous neck dissection, sacrifice of the strap muscles or of a patch of oesophageal muscle layer. We advocate a sternocleidomastoid flap to cover the anastomosis. Cricotracheal resection for subglottic invasion can be curative with good functional outcomes, even for the advanced stages of thyroid cancer. Endoscopic debulking of the airway prior to the procedure avoids tracheotomy.

Thyroid cancer mortality and incidence: a global overview.

In most areas of the world, thyroid cancer incidence has been appreciably increasing over the last few decades, whereas mortality has steadily declined. We updated global trends in thyroid cancer mortality and incidence using official mortality data from the World Health Organization (1970-2012) and incidence data from the Cancer Incidence in Five Continents (1960-2007). Male mortality declined in all the major countries considered, with annual percent changes around -2/-3% over the last decades. Only in the United States mortality declined up to the mid 1980s and increased thereafter. Similarly, in women mortality declined in most countries considered, with APCs around -2/-5% over the last decades, with the exception of the UK, the United States and Australia, where mortality has been declining up to the late 1980s/late 1990s to level off (or increase) thereafter. In 2008-2012, most countries had mortality rates (age-standardized, world population) between 0.20 and 0.40/100,000 men and 0.20 and 0.60/100,000 women, the highest rates being in Latvia, Hungary, the Republic of Moldova and Israel (over 0.40/100,000) for men and in Ecuador, Colombia and Israel (over 0.60/100,000) for women. In most countries, a steady increase in the incidence of thyroid cancer (mainly papillary carcinomas) was observed in both sexes. The declines in thyroid cancer mortality reflect both variations in risk factor exposure and changes in the diagnosis and treatment of the disease, while the increases in the incidence are likely due to the increase in the detection of this neoplasm over the last few decades.

Thyroid hormone in biodegradable nerve guides stimulates sciatic nerve regeneration: a potential therapeutic approach for human peripheral nerve injuries.

It has been already demonstrated that thyroid hormone (T3) is one of the most important stimulating factors in peripheral nerve regeneration. We have recently shown that local administration of T3 in silicon tubes at the level of the transected rat sciatic nerve enhanced axonal regeneration and improved functional recovery. Silicon, however, cannot be used in humans because it causes a chronic inflammatory reaction. Therefore, in order to provide future clinical applications of thyroid hormone in human peripheral nerve lesions, we carried out comparative studies on the regeneration of transected rat sciatic nerve bridged either by biodegradable P(DLLA-(-CL) or by silicon nerve guides, both guides filled with either T3 or phosphate buffer. Our macroscopic observation revealed that 85% of the biodegradable guides allowed the expected regeneration of the transected sciatic nerve. The morphological, morphometric and electrophysiological analysis showed that T3 in biodegradable guides induces a significant increase in the number of myelinated regenerated axons (6862 +/- 1831 in control vs. 11799 +/- 1163 in T3-treated). Also, T3 skewed the diameter of myelinated axons toward larger values than in controls. Moreover, T3 increases the compound muscle action potential amplitude of the flexor and extensor muscles of the treated rats. This T3 stimulation in biodegradable guides was equally well to that obtained by using silicone guides. In conclusion, the administration of T3 in biodegradable guides significantly improves sciatic nerve regeneration, confirming the feasibility of our technique to provide a serious step towards future clinical application of T3 in human peripheral nerve injuries.

Transformation of a microprolactinoma into a mixed growth hormone and prolactin-secreting pituitary adenoma.

Combined prolactin (PRL) and growth hormone (GH) secretion by a single pituitary tumor can occur in approximately 5% of cases. However, in all previously reported patients, combined secretion of both hormones was present at the time of diagnosis. Here we describe a patient initially diagnosed with a pure prolactin-secreting microadenoma, who experienced the progressive apparition of symptomatic autonomous GH secretion while on intermittent long term dopamine agonist therapy. She was operated on, and immunohistochemical analysis of tumor tissue confirmed the diagnosis of pituitary adenoma with uniform co-staining of all cells for both GH and PRL. This patient represents the first documented occurrence of asynchronous development of combined GH and PRL secretion in a pituitary adenoma. Although pathogenic mechanisms implicated remain largely speculative, it emphasizes the need for long term hormonal follow up of patients harboring prolactinomas.

Thyroid hormone enhances transected axonal regeneration and muscle reinnervation following rat sciatic nerve injury.

Improvement of nerve regeneration and functional recovery following nerve injury is a challenging problem in clinical research. We have already shown that following rat sciatic nerve transection, the local administration of triiodothyronine (T3) significantly increased the number and the myelination of regenerated axons. Functional recovery is a sum of the number of regenerated axons and reinnervation of denervated peripheral targets. In the present study, we investigated whether the increased number of regenerated axons by T3-treatment is linked to improved reinnervation of hind limb muscles. After transection of rat sciatic nerves, silicone or biodegradable nerve guides were implanted and filled with either T3 or phosphate buffer solution (PBS). Neuromuscular junctions (NMJs) were analyzed on gastrocnemius and plantar muscle sections stained with rhodamine alpha-bungarotoxin and neurofilament antibody. Four weeks after surgery, most end-plates (EPs) of operated limbs were still denervated and no effect of T3 on muscle reinnervation was detected at this stage of nerve repair. In contrast, after 14 weeks of nerve regeneration, T3 clearly enhanced the reinnervation of gastrocnemius and plantar EPs, demonstrated by significantly higher recovery of size and shape complexity of reinnervated EPs and also by increased acetylcholine receptor (AChRs) density on post synaptic membranes compared to PBS-treated EPs. The stimulating effect of T3 on EP reinnervation is confirmed by a higher index of compound muscle action potentials recorded in gastrocnemius muscles. In conclusion, our results provide for the first time strong evidence that T3 enhances the restoration of NMJ structure and improves synaptic transmission.

Role of retinoic acid signaling pathway in endoderm antero-posterior patterning

Summary : During vertebrate embryonic development, the endoderm gives rise to the digestive tract and associated organs such as thyroid, lung, liver and pancreas. Earlier studies have shown that extracellular signals coming from the lateral plate mesoderm pattern the endoderm along the antero-posterior axis specifying different organ primordia. An early sign of patterning is the expression of organ-specific genes in restricted endoderm domains. In this study, we focused on the role of the retinoic acid (RA) signaling pathway in the regionalization of the future gut tube along the main body axis. We show that the RA-synthesizing enzyme Raldh2 is expressed in mesoderm close to the endoderm during gastrulation and during somitogenesis. During the same period, all retinoic acid receptors (RARs), which directly activate gene transcription, are expressed in endoderm suggesting that endoderm can be responsive to RA. Activation or inhibition of RA signaling was achieved by adding RA or RAR inhibitors tither on beads or in the medium to cultured chick embryos. Branchial arch (BA) endoderm markers were shifted posteriorly upon depletion of RA at gastrulation, but were not shifted after this stage. Conversely, exposure to exogenous RA repressed the most-anterior BA markers and shifted more posterior BA markers anteriorly. This suggests that graded levels of RA activity in the foregut define gene boundaries and expression levels. The posterior foregut and midget markers Pdxl and CdxA require RA for their expression, but elevated RA does not shift their expression domain along the antero-posterior axis. In addition, we investigated if RA signaling pathway interacts with other signaling pathways to pattern the endoderm. Although both RA and FGFs block anterior foregut marker expression, our experiments suggest that FGF signaling does not depend on RA in anterior endoderm. To validate our chick data in mammalians and evaluate whether RA acts directly on endoderm, we have further generated a conditional loss-of-function system in the mouse, which is still under examination.

Sports-related chronic repetitive head trauma as a cause of pituitary dysfunction.

Traumatic brain injury (TBI) is recognized as a cause of hypopituitarism even after mild TBI. Although over the past decade, a growing body of research has detailed neuroendocrine changes induced by TBI, the mechanisms and risk factors responsible for this pituitary dysfunction are still unclear. Around the world, sports-especially combative sports-are very popular. However, sports are not generally considered as a cause of TBI in most epidemiological studies, and the link between sports-related head trauma and hypopituitarism has not been investigated until recently. Thus, there is a paucity of data regarding this important concern. Because of the large number of young sports participants with near-normal life expectancy, the implications of undiagnosed or untreated postconcussion pituitary dysfunction can be dramatic. Understanding the pathophysiological mechanisms and risk factors of hypopituitarism caused by sports injuries is thus an important issue that concerns both medical staff and sponsors of sports. The aim of this paper was to summarize the best evidence for understanding the pathophysiological mechanisms and to discuss the current data and recommendations on sports-related head trauma as a cause of hypopituitarism.

Involvement of the CXCR7/CXCR4/CXCL12 Axis in the Malignant Progression of Human Neuroblastoma.

Neuroblastoma (NB) is a typical childhood and heterogeneous neoplasm for which efficient targeted therapies for high-risk tumors are not yet identified. The chemokine CXCL12, and its receptors CXCR4 and CXCR7 have been involved in tumor progression and dissemination. While CXCR4 expression is associated to undifferentiated tumors and poor prognosis, the role of CXCR7, the recently identified second CXCL12 receptor, has not yet been elucidated in NB. In this report, CXCR7 and CXCL12 expressions were evaluated using a tissue micro-array including 156 primary and 56 metastatic NB tissues. CXCL12 was found to be highly associated to NB vascular and stromal structures. In contrast to CXCR4, CXCR7 expression was low in undifferentiated tumors, while its expression was stronger in matured tissues and specifically associated to differentiated neural tumor cells. As determined by RT-PCR, CXCR7 expression was mainly detected in N-and S-type NB cell lines, and was slightly induced upon NB cell differentiation in vitro. The relative roles of the two CXCL12 receptors were further assessed by overexpressing CXCR7 or CXCR4 receptor alone, or in combination, in the IGR-NB8 and the SH-SY5Y NB cell lines. In vitro functional analyses indicated that, in response to their common ligand, both receptors induced activation of ERK1/2 cascade, but not Akt pathway. CXCR7 strongly reduced in vitro growth, in contrast to CXCR4, and impaired CXCR4/CXCL12-mediated chemotaxis. Subcutaneous implantation of CXCR7-expressing NB cells showed that CXCR7 also significantly reduced in vivo growth. Moreover, CXCR7 affected CXCR4-mediated orthotopic growth in a CXCL12-producing environment. In such model, CXCR7, in association with CXCR4, did not induce NB cell metastatic dissemination. In conclusion, the CXCR7 and CXCR4 receptors revealed specific expression patterns and distinct functional roles in NB. Our data suggest that CXCR7 elicits anti-tumorigenic functions, and may act as a regulator of CXCR4/CXCL12-mediated signaling in NB.

In vitro functionality of isolated embryonic hypothalamic vasopressinergic and oxytocinergic neurons: modulatory effects of brain-derived neurotrophic factor and angiotensin II.

There are only a few studies on the ontogeny and differentiation process of the hypothalamic supraoptic-paraventriculo-neurohypophysial neurosecretory system. In vitro neuron survival improves if cells are of embryonic origin; however, surviving hypothalamic neurons in culture were found to express small and minimal amounts of arginine-vasopressin (AVP) and oxytocin (OT), respectively. The aim of this study was to develop a primary neuronal culture design applicable to the study of magnocellular hypothalamic system functionality. For this purpose, a primary neuronal culture was set up after mechanical dissociation of sterile hypothalamic blocks from 17-day-old Sprague-Dawley rat embryos (E17) of both sexes. Isolated hypothalamic cells were cultured with supplemented (B27)-NeuroBasal medium containing an agent inhibiting non-neuron cell proliferation. The neurosecretory process was characterized by detecting AVP and OT secreted into the medium on different days of culture. Data indicate that spontaneous AVP and OT release occurred in a culture day-dependent fashion, being maximal on day 13 for AVP, and on day 10 for OT. Interestingly, brain-derived neurotrophic factor (BDNF) and Angiotensin II (A II) were able to positively modulate neuropeptide output. Furthermore, on day 17 of culture, non-specific (high-KCl) and specific (Angiotensin II) stimuli were able to significantly (P < 0.05) enhance the secretion of both neuropeptides over respective baselines. This study suggests that our experimental design is useful for the study of AVP- and OT-ergic neuron functionality and that BDNF and A II are positive modulators of embryonic hypothalamic cell development.

Thyroid hormone reduces the loss of axotomized sensory neurons in dorsal root ganglia after sciatic nerve transection in adult rat.

We have shown that a local administration of thyroid hormones (T3) at the level of transected rat sciatic nerve induced a significant increase in the number of regenerated axons. To address the question of whether local administration of T3 rescues the axotomized sensory neurons from death, in the present study we estimated the total number of surviving neurons per dorsal root ganglion (DRG) in three experimental group animals. Forty-five days following rat sciatic nerve transection, the lumbar (L4 and L5) DRG were removed from PBS-control, T3-treated as well as from unoperated rats, and serial sections (1 microm) were cut. The physical dissector method was used to estimate the total number of sensory neurons in the DRGs. Our results revealed that in PBS-control rats transection of sciatic nerve leads to a significant (P < 0.001) decrease in the mean number of sensory neurons (8743.8 +/- 748.6) compared with the number of neurons in nontransected ganglion (mean 13,293.7 +/- 1368.4). However, administration of T3 immediately after sciatic nerve transection rescues a great number of axotomized neurons so that their mean neuron number (12,045.8 +/- 929.8) is not significantly different from the mean number of neurons in the nontransected ganglion. In addition, the volume of ganglia showed a similar tendency. These results suggest that T3 rescues a high number of axotomized sensory neurons from death and allows these cells to grow new axons. We believe that the relative preservation of neurons is important in considering future therapeutic approaches of human peripheral nerve lesion and sensory neuropathy.

How do thyroid hormone receptors bind to structurally diverse response elements?

Three classes of thyroid hormone response elements have been described. They are composed of two half-sites arranged either as a palindromic, a direct repeat or as an inverted palindromic array. Receptor homodimers as well as heterodimers can bind to all three types of response element. While the ligand binding domain of the receptors provides the major dimerization surface, asymmetric contacts between the DNA binding domains are necessary for binding to a direct repeat. Moreover, some recent findings suggest that in TR, compared to RXR, the ligand binding domain has a 180 degrees rotation with respect to the DNA binding domain. This feature could explain the preferential binding of the RXR-TR heterodimer to the direct repeat response element, in which RXR exclusively binds the 5' half-site, and of the TR homodimer to the inverted palindrome response element.

Chirurgie viscérale. Chirurgie thyroïdienne et parathyroïdienne: place de la chirurgie minimale invasive [Update in thyroid and parathyroid surgery: the role for minimally invasive surgery].

Thyroid and parathyroid surgery takes an important place in general surgery. Preservation of essential cervical structures and cosmetic of outcomes of cervical incisions are major concern. Several minimally invasive strategies have been developed recently but their acceptance in the surgical community is low. Their main advantages are focused tissue dissection and improved cosmetics. In this review, management and surgical indications of thyroid nodules and parathyroid adenomas are discussed. The various minimally invasive techniques are described and their current indications are reviewed.

Adiposity in children born small for gestational age.

Epidemiological studies indicate that children born small for gestational age (SGA) have an increased risk of metabolic and cardiovascular disorders as adults. This suggests that foetal undernutrition leads to permanent metabolic alterations, which predispose to metabolic abnormalities upon exposure to environmental factors such as low physical activity and/or high-energy intake in later life (thrifty phenotype hypothesis). However, this relationship is not restricted to foetal undernutrition or intrauterine growth retardation, but is also found for children born premature, or for high birth weight children. Furthermore, early post-natal nutrition, and more specifically catch-up growth, appear to modulate cardiovascular risk as well. Intrauterine growth retardation can be induced in animal models by energy/protein restriction, or ligation of uterine arteries. In such models, altered glucose homeostasis, including low beta-cell mass, low insulin secretion and insulin resistance is observed after a few weeks of age. In humans, several studies have confirmed that children born SGA have insulin resistance as adolescents and young adults. Alterations of glucose homeostasis and increased lipid oxidation can indeed be observed already in non-diabetic children born SGA at early pubertal stages. These children also have alterations of stature and changes in body composition (increased fat mass), which may contribute to the pathogenesis of insulin resistance. Permanent metabolic changes induced by foetal/early neonatal nutrition (metabolic inprinting) may involve modulation of gene expression through DNA methylation, or alterations of organ structure. It is also possible that events occurring during foetal/neonatal development lead to long-lasting alterations of the hypothalamo-pituitary-adrenal axis or the hypothalamo-pituitary-insulin-like growth factor-1 axis.

Activation of a HIF1alpha-PPARgamma axis underlies the integration of glycolytic and lipid anabolic pathways in pathologic cardiac hypertrophy.

Development of cardiac hypertrophy and progression to heart failure entails profound changes in myocardial metabolism, characterized by a switch from fatty acid utilization to glycolysis and lipid accumulation. We report that hypoxia-inducible factor (HIF)1alpha and PPARgamma, key mediators of glycolysis and lipid anabolism, respectively, are jointly upregulated in hypertrophic cardiomyopathy and cooperate to mediate key changes in cardiac metabolism. In response to pathologic stress, HIF1alpha activates glycolytic genes and PPARgamma, whose product, in turn, activates fatty acid uptake and glycerolipid biosynthesis genes. These changes result in increased glycolytic flux and glucose-to-lipid conversion via the glycerol-3-phosphate pathway, apoptosis, and contractile dysfunction. Ventricular deletion of Hif1alpha in mice prevents hypertrophy-induced PPARgamma activation, the consequent metabolic reprogramming, and contractile dysfunction. We propose a model in which activation of the HIF1alpha-PPARgamma axis by pathologic stress underlies key changes in cell metabolism that are characteristic of and contribute to common forms of heart disease.