[Adrenalectomy for adrenal metastases: is the laparoscopic approach beneficial for all patients?]. / Surrénalectomie pour métastases surrénaliennes: la voie d'abord laparoscopique est-elle bénéfique pour tous les patients ?

INTRODUCTION: Laparoscopy has become the gold-standard approach for excision of benign adrenal tumors but the question of its safety for malignant lesions is still controversial. Our aim was to evaluate the oncologic outcome of laparoscopic adrenalectomy for adrenal metastasis and to look for predictors of a negative surgical outcome. PATIENTS AND METHODS: We retrospectively reviewed the charts of all patients who underwent laparoscopic adrenalectomy for suspicion of adrenal metastasis between 2007 and 2013 at a single academic institution. Recurrence-free survival (RFS) and cancer-specific survival (CSS) were estimated using the Kaplan-Meier method. Univariate analysis was performed to determine risk factors of negative surgical outcome (positive surgical margins, complications, conversion, significant blood loss) and predictors of RFS and CSS. RESULTS: Thirteen patients underwent 14 laparoscopic adrenalectomies. All patients were operated by a single highly experienced surgeon. Complications occurred in 2 patients (15%): 2 blood transfusions (Clavien-score=2). There were 3 positive surgical margins (21%). Mean length of hospital stay was 4.3 days. Unadjusted RFS and CSS were respectively 48.4% and 83.3% at 1 year, 39.5% and 66.7% at 5 years. In univariate analysis, tumor size was the only risk factor of complication (P=.009) and conversion (P=0.009). Capsule invasion and tumor size were risk factors of positive surgical margins (P=0.01 and P<0.0001). One hundred percent of complications, conversion and positive surgical margins occurred in tumor>7.5 cm on preoperative CT-scan. No predictors of RFS and CSS was found in univariate analysis. CONCLUSION: Laparoscopic adrenalectomy for adrenal metastasis achieves good surgical and oncologic outcomes. When performed by highly experienced surgeon, complications and positive surgical margins occur only in tumors>7.5 cm. These patients may benefit from an open surgical approach.

[Subretinal hemorrhage after intravitreal injection of anti-VEGF for age-related macular degeneration: a retrospective study]. / Hématomes maculaires après injections intravitréennes d'anti-VEGF pour dégénérescence maculaire liée à l'âge : série rétrospective.

INTRODUCTION: Prescription of anti-VEGF treatments have increased substantially over the past few years in treatment of wet age-related macular degeneration. We report the occurrence of macular hemorrhages after one year of use of anti-VEGF intravitreal injections, mainly for subfoveal choroidal neovascularization. MATERIAL AND METHODS: Four hundred forty five injections were given over one year (from 15 March 2007 to 15 March 2008), for age-related macular degeneration, retinal vascular occlusion, diabetic retinopathy, neovascular glaucoma, and idiopathic macular choroidal neovascularization; distributed as follows: 11.5% Bevacizumab, 18.6% Pegaptanib, 19.3% Triamcinolone, and 50.6% Ranibizumab. RESULTS: Six macular hemorrhages were observed, resulting in to a sharp decrease in visual acuity (20/400), with loss of five lines. All occurred after one injection of nonselective anti-VEGF (Ranibizumab) on already treated eyes (four previous injections on average, +/- photodynamic therapy). All were secondary to occult choroidal neovascularization or a large pigment epithelial detachment. Three patients presented a pigment epithelial tear. DISCUSSION: Anti-VEGF intravitreal injections can lead to pigment epithelial tears in case of large pigment epithelial detachment, especially with a small feeder vessel or with large occult choroidal neovascularization. The authors discuss the possible implications of anti-VEGF when macular hematoma occurs: retraction of choroidal neovascularization and alteration of physiological retinal vascularization. CONCLUSION: Macular hematoma affects visual prognosis in age-related macular degeneration. It may follow intravitreal anti-VEGF injection with large occult neovascularization, especially in previously treated eyes. Injection in large pigment epithelial detachment may cause a risk of epithelial tear. Other studies are necessary to evaluate the role of the nonselective anti-VEGF in the incidence of macular hematoma.

Mouse vanin-1 is cytoprotective for islet beta cells and regulates the development of type 1 diabetes.

AIMS/HYPOTHESIS: Islet cell death is a key initiating and perpetuating event in type 1 diabetes and involves both immune-mediated and endogenous mechanisms. The epithelial pantetheinase vanin-1 is proinflammatory and cytoprotective via cysteamine release in some tissues. We investigated the impact of a vanin-1 deficiency on islet death and type 1 diabetes incidence. METHODS: Vanin-1-deficient mice were produced and tested in drug-induced and autoimmune diabetes models. The contribution of vanin-1 to islet survival versus immune responses was evaluated using lymphocyte transfer and islet culture experiments. RESULTS: The vanin-1/cysteamine pathway contributes to the protection of islet beta cells from streptozotocin-induced death in vitro and in vivo. Furthermore, vanin-1-deficient NOD mice showed a significant aggravation of diabetes, which depended upon loss of vanin-1 expression by host tissues. This increased islet fragility was accompanied by greater CD4+ insulitis without impairment of regulatory cells. Addition of cystamine, the product of pantetheinase activity, protected islets in vitro and compensated for vanin-1 deficiency in vivo. CONCLUSIONS/INTERPRETATION: This study unravels a major cytoprotective role of cysteamine for islet cells and suggests that modulation of pantetheinase activity may offer alternative strategies to maintain islet cell homeostasis.

[Internal carotid artery dissection on arterial fibromuscular dysplasia causing a central retinal artery occlusion: a case report]. / Oblitération de l'artère centrale de la rétine secondaire à une dissection de la carotide interne sur fibrodysplasie artérielle.

INTRODUCTION: We report a case of a 66-year-old woman presenting a central retinal artery occlusion with no cardiovascular risk factor, with assessment using supra-aortic artery ultrasonography showing total internal carotid artery thrombosis. OBSERVATION: When vascular thrombosis risk factors are absent, more in-depth assessment such as a supra-aortic artery angioscan can provide the diagnosis of arterial dissection on arterial fibromuscular dysplasia. CONCLUSION: Central retinal artery occlusion is a rare but severe pathology. Therefore it is very important not to neglect the etiological assessment, because it can be the revealing element of a severe pathology.

Vanin-1-/- mice exhibit a glutathione-mediated tissue resistance to oxidative stress.

Vanin-1 is an epithelial ectoenzyme with pantetheinase activity and generating the amino-thiol cysteamine through the metabolism of pantothenic acid (vitamin B(5)). Here we show that Vanin-1(-/-) mice, which lack cysteamine in tissues, exhibit resistance to oxidative injury induced by whole-body gamma-irradiation or paraquat. This protection is correlated with reduced apoptosis and inflammation and is reversed by treating mutant animals with cystamine. The better tolerance of the Vanin-1(-/-) mice is associated with an enhanced gamma-glutamylcysteine synthetase activity in liver, probably due to the absence of cysteamine and leading to elevated stores of glutathione (GSH), the most potent cellular antioxidant. Consequently, Vanin-1(-/-) mice maintain a more reducing environment in tissue after exposure to irradiation. In normal mice, we found a stress-induced biphasic expression of Vanin-1 regulated via antioxidant response elements in its promoter region. This process should finely tune the redox environment and thus change an early inflammatory process into a late tissue repair process. We propose Vanin-1 as a key molecule to regulate the GSH-dependent response to oxidative injury in tissue at the epithelial level. Therefore, Vanin/pantetheinase inhibitors could be useful for treatment of damage due to irradiation and pro-oxidant inducers.

[Penicillium chrysogenum endophthalmitis: a case report]. / Endophtalmie à Penicillium chrysogenum: à propos d'un cas.

We report a case of Penicillium chrysogenum endophthalmitis after penetrating ocular trauma in a 9-year-old child, describing the initial management and the therapeutic adaptation after biopsy culture. After a review of endophthalmitis treatment, we discuss mycotic endophthalmitis treatment and recommend the use of intravitreal antibiotics. In this case, we used amphotericin B to treat the fungal disorder with success.

[Ocular metastasis of cutaneous melanoma]. / Métastase oculaire d'un mélanome cutané.

We report a case of vitreal metastases from cutaneous melanoma. We describe the clinical findings and the histological aspects of the lesions, which allows us to discuss the diagnosis of masquerade syndrome and highlight the diagnostic importance of vitreous biopsy.

Ep-CAM transfection in thymic epithelial cell lines triggers the formation of dynamic actin-rich protrusions involved in the organization of epithelial cell layers.

Thymic epithelium is organized in a highly connected three-dimensional network through which thymocytes differentiate. The molecular mechanisms underlying this organization are still unknown. In thymic medulla, a major site of tolerance induction, the development of the epithelial cell net is tightly regulated by the needs of thymocyte selection. These reticulated epithelial cells express high levels of the Ep-CAM molecule. Using different thymic epithelial cell lines as a model system, we found that transfection of Ep-CAM enhances cell growth and leads to a rapid reorganization of the actin cytoskeleton by inducing the formation of numerous stress fibers and long cell protrusions. Finally, the crosslinking of the extracellular domain of a chimeric CD25ec/Ep-CAMic molecule is sufficient to trigger the formation of protrusions. These results suggest that expression of Ep-CAM might balance the organizing capacity of cadherin molecules and may be participating in the formation of a dynamic stromal cell network in the thymus.

Pantetheinase activity of membrane-bound Vanin-1: lack of free cysteamine in tissues of Vanin-1 deficient mice.

Pantetheinase (EC 3.5.1.-) is an ubiquitous enzyme which in vitro has been shown to recycle pantothenic acid (vitamin B5) and to produce cysteamine, a potent anti-oxidant. We show that the Vanin-1 gene encodes pantetheinase widely expressed in mouse tissues: (1) a pantetheinase activity is specifically expressed by Vanin-1 transfectants and is immunodepleted by specific antibodies; (2) Vanin-1 is a GPI-anchored pantetheinase, and consequently an ectoenzyme; (3) Vanin-1 null mice are deficient in membrane-bound pantetheinase activity in kidney and liver; (4) in these organs, a major metabolic consequence is the absence of detectable free cysteamine; this demonstrates that membrane-bound pantetheinase is the main source of cysteamine in tissues under physiological conditions. Since the Vanin-1 molecule was previously shown to be involved in the control of thymus reconstitution following sublethal irradiation in vivo, this raises the possibility that Vanin/pantetheinase might be involved in the regulation of some immune functions maybe in the context of the response to oxidative stress.

An ESTs description of the new Vanin gene family conserved from fly to human.

Circulation and tissue colonization are essential properties of lymphoid cells and involve major families of adhesion molecules (e.g. , integrin, selectin, mucin-like, and molecules from the immunoglobulin superfamily). The mouse Vanin-1 molecule was recently identified and found to be involved in the colonization of the thymus by hematopoietic precursor cells. Here we show based on computational analysis of EST sequence database resources that Vanin-1 belongs to a new family of related molecules present from drosophila to human. This family includes the amidase enzyme Biotinidase, and a central protein domain is shared between Vanin and Nitrilase families, suggesting that Vanin molecules might bear an enzymatic activity. Five of these molecules were new uncharacterized cDNA sequences only described as ESTs. The three human Vanin genes map to the same region of Chromosome 6q. The detailed results are consultable at the VANIN web page (http://tagc. univ-mrs.fr/pub/vanin/).

Two human genes related to murine vanin-1 are located on the long arm of human chromosome 6.

We report here the identification of two distinct human cDNAs, called VNN1 and VNN2, related to the recently described mouse Vanin-1 molecule involved in lymphocyte migration (M. Aurrand-Lions et al., 1996, Immunity 5: 391-405). Tissue distribution of the expression of these two human Vanin-like genes is differential. Since Vanin-1 shares significant homologies with human biotinidase (BTD), we describe here a new family of related genes including at least four members: mouse Vanin-1, VNN1, VNN2, and BTD. We have mapped the murine locus encompassing the Vanin-1 gene on mouse chromosome 10 in position A2B1. The two human Vanin-like genes are closely linked, since they were found on the same YAC clone and colocalized on human chromosome 6q23-q24 known to contain several genetic alterations linked to the progression of metastatic human cancers.

Thymocytes and RelB-dependent medullary epithelial cells provide growth-promoting and organization signals, respectively, to thymic medullary stromal cells.

The thymic medulla is composed of distinct epithelial cell subsets, defined in this report by the reactivity of two novel antibodies, 95 and 29, raised against mouse thymic epithelial cell lines. These antibodies were used to probe the development of medulla in wild-type or mutant thymuses. In CD3 epsilon-deficient mice where thymocyte maturation is arrested at the CD4- CD8- stage, few scattered 95+ and 29+ epithelial cells are found. When few mature thymocytes develop as in CD3- zeta/eta mice, expansion and organization of 95+ but not 29+ cells, becomes detectable. In RelB-deficient mice, T cell maturation proceeds normally but negative selection is inefficient due to the lack of thymic medulla and dendritic cells. Strikingly, 29+ epithelial cells are absent and 95+ medullary epithelial cells are scattered throughout the thymus, intermingling with CDR1+ cortical epithelium. In chimeric mice lacking only dendritic cells, the corticomedullary junction persists and both 95+ and 29+ epithelial cells are localized in the medulla. These results suggest that two types of signals are required for development of thymic medulla. A growth signal depends upon the presence of maturing thymocytes, but organization of the thymic medulla requires the presence of activated 29+ medullary epithelial cells.

Efficacy and safety of a low-molecular-weight heparin and standard unfractionated heparin for prophylaxis of postoperative venous thromboembolism: European multicenter trial.

A randomized, double-blind multicenter trial was performed to compare the safety and efficacy of a new low-molecular-weight heparin (LMWH) (LU 47311, Clivarine) and standard unfractionated heparin for the prophylaxis of postoperative venous thromboembolism. Altogether 1351 patients scheduled to undergo abdominal surgery were included. Main outcome measures included the incidence of thromboembolic events (deep vein thrombosis, pulmonary embolism, or both) and bleeding complications, including wound hematoma. A total of 655 patients received 1750 anti-Xa IU of LMWH plus a placebo injection daily; 677 patients received 5000 IU of unfractionated heparin (UFH) twice a day. Both drugs were found to be equally effective, as 4.7% of patients in the LMWH group and 4.3% in the UFH group developed postoperative thromboembolic complications. However, the incidence of bleeding complications was significantly reduced in the LMWH group: 55 (8.3%) patients in the LMWH group and 80 (11.8%) in the UFH group developed bleeding complications, a relative risk (RR) of 0.70 (95% CI 0.51-0.97;p = 0.03); wound hematoma occurred in 29 (4.4%) of the LMWH group compared with 55 (7.7%) in those in the UFH group for an RR of 0.57 (95% CI 0.37-0.88;p = 0.01). This study confirmed that a very low dose of 1750 anti-Xa IU daily of this new LMWH is as effective as 10,000 IU of UFH for preventing postoperative deep vein thrombosis. At this dose its administration is associated with a significant reduction in the risk of bleeding including wound hematoma.

Vanin-1, a novel GPI-linked perivascular molecule involved in thymus homing.

Migration of hematopoietic precursor cells to the thymus is shown to depend upon a novel molecule called Vanin-1 expressed by perivascular thymic stromal cells. An anti-Vanin-1 antibody blocks the binding of pro-T cells to thymic sections in vitro, the in vivo accumulation of bone marrow cells around cortical thymic vessels, and long-term thymic regeneration. Thus, it interferes with the entry, and not the differentiation, of hematopoietic precursor cells. The Vanin-1 gene codes for a GPI-anchored 70 kDa protein that shows homology only with human biotinidase. Transfection of thymic stromal cells with the Vanin-1 cDNA enhances thymocyte adhesion in vitro. These data suggest that Vanin-1 regulates late adhesion steps of thymus homing under physiological, noninflammatory conditions.

Localization of two tyrosine kinase receptor genes with respect to the 5q35 chromosomal breakpoint of Ki-1 lymphoma cell lines.

The consistency of the breakpoint on chromosome 5 at band 5q35 occurring in Ki-1 non-Hodgkin's lymphomas is highly suggestive of the involvement of a locally altered gene in this disease. In this study, we analyzed the potential involvement, in the translocation, of two receptor tyrosine kinase genes and putative oncogenes, FLT4 and FGFR4, previously localized near this breakpoint. Fluorescence in situ chromosomal hybridization allowed us to refine their localization to sub-band 5q35.3 and to show that both genes are translocated to the derivative chromosomes in Ki-1 cell lines containing either a t(2;5) or a t(3;5). Pulsed-field gel electrophoresis showed that the FLT4 and FGFR4 genes are not physically linked, nor are they altered by the translocation. Finally, Northern blot analysis showed that neither FLT4 nor FGFR4 is expressed in the Ki-1 cell lines, suggesting that they are not implicated in the genesis of Ki-1 lymphomas.

The FLT4 gene encodes a transmembrane tyrosine kinase related to the vascular endothelial growth factor receptor.

Three receptor tyrosine kinases, FLT1, FLK1 and FLT4, contain seven immunoglobin-like domains in their extracellular region and are strongly related by sequence similarities to each other and, to a lesser degree, to the class III receptors CSF1R/FMS, PDGFR, SLFR/KIT and FLT3/FLK2. They constitute a family of receptors putatively involved in the growth regulation of endothelial cells. We describe here the structure and pattern of expression of the human FLT4 gene. Two FLT4 transcripts of 5.8 and 4.5 kb are expressed in the human placenta and several hematopoietic cell lines. In mouse, a 5.8-kb transcript is expressed in a variety of tissues. A translational product 1298 amino acids in length is predicted to be encoded by the largest open reading frame. The FLT4 protein, when transiently expressed in Cos-7 cells and immunoprecipitated with a FLT4-specific rabbit immune serum, has an apparent molecular weight of 170 kDa.