Marie-Christine Machet

PREOPERATIVE MEASUREMENT OF THICKNESS OF CUTANEOUS MELANOMA USING HIGH-RESOLUTION 20 MHZ ULTRASOUND IMAGING: A MONOCENTER PROSPECTIVE STUDY AND SYSTEMATIC REVIEW OF THE LITERATURE

Histologic measurement of the thickness of melanoma is a major prognostic factor and governs the size of the surgical excision (1cm for melanomas less than 1 mm thick, 2 cm for melanomas thicker than 2 mm and 3 cm beyond 4 mm). To determine whether high-resolution ultrasound can be used to predict surgical margins and, thus, to operate on patients in a single procedure avoiding further re-excision, we performed a systematic review of studies published from January 1987 to June 2007 and a prospective study. The systematic review selected 14 studies comparing histologic and ultrasound measurements and showing correlation coefficients generally greater than 0.9. Data available from 7 of the 14 studies (total 869 patients) showed predictive values of adequate margins in at least 72% of lesions using preoperative measurement of ultrasound thickness. The prospective study included 31 patients referred with a primary melanoma from March 2005 to March 2007. Ultrasound measurement of thickness was possible except for thin melanomas (<0.4 mm) in areas with marked photoaging, in the plantar zone, and in the case of very thick melanomas exceeding the explored depth (7.6 mm). The average thickness was 1.96 mm measured by ultrasound (SD: 2.15) and 1.95 mm by histology (SD: 2.62) and the Bland and Altman graph showed moderate agreement between ultrasound and histology. Limits of agreement were estimated at -1.4 and +1.8, corresponding to relative limits of agreement of -40 to +80%. Ultrasound predicted appropriate margins (1, 2 or 3 cm wide according to sonometric thickness) in 26 of the 31 subjects (84%, 95% CI 66-95). Preoperative high-resolution ultrasound is a noninvasive examination that can help in choosing appropriate surgical margins and should reduce the need of partial or excisional biopsy before surgery, and the need for further re-excision.

Hemin decreases cardiac oxidative stress and fibrosis in a rat model of systemic hypertension via PI3K/Akt signalling

AIMSnAngiotensin II induces cardiac myocyte apoptosis and hypertrophy, which contribute to heart failure, possibly through enhanced oxidative stress. The aim of this work was to assess the impact of hemin (heme oxygenase-1 inducer) on NADPH oxidase activation, cardiac oxidative stress, and development of fibrosis in a rat model of renovascular hypertensive cardiomyopathy in comparison to an anti-hypertensive reference treatment with losartan.nnnMETHODS AND RESULTSnA 3 week hemin treatment was tested in an angiotensin II-dependent hypertensive rat model and a cellular model of neonatal rat cardiomyocytes stimulated by angiotensin II. Our findings demonstrate that hemin prevented development of intercellular fibrosis, expression of collagen I, and disorganization of intracellular fibres. Oxidative stress and apoptosis evaluated in hypertensive myocardial tissue were decreased by hemin. The reference treatment with the angiotensin II receptor (AT(1)) antagonist (losartan) was less effective than hemin in prevention of fibrosis and oxidative stress, although it was more effective in reducing hypertension. Rac-1 activation and, subsequently, NADPH oxidase activity were further decreased with hemin than with losartan. Hemin enhanced the expression of phosphoinositide 3-kinase (PI3K) p85 regulatory subunit, in contrast to losartan. The PI3K/Akt signalling pathway activation by hemin was related to heme oxygenase-1 activation and an increase in biliverdin reductase, and its inhibition by LY294002 reversed the effects of hemin on collagen I and caspase-3 expression. Finally, hemin increased Akt activation, and concomitantly decreased RhoA and p38 mitogen-activated protein kinase activation.nnnCONCLUSIONnWe confirmed a positive effect of hemin on oxidative cardiac damage, apoptosis, and fibrosis induced by hypertension by modulating the NADPH oxidase activation through enhanced expression of the PI3K p85 regulatory subunit.

Immunostaining With Antibodies to Desmoglein Provides the Diagnosis of Drug-Induced Pemphigus and Allows Prediction of Outcome

No tool is available to diagnose drug-induced pemphigus (DIP) and to predict its outcome after the withdrawal of the culprit drugs. This retrospective pemphigus case series study compared cutaneous/mucosal immunostaining of a monoclonal antibody directed toward desmogleins 1 and 3 (32-2B) in 37 patients with DIP and 56 patients with idiopathic pemphigus. There was a significant difference between the groups in terms of pruritus, superficial form, mucosal involvement, and circulating antibodies. 32-2B staining disclosed a patchy pattern in 47 (84%) of idiopathic pemphigus cases and in 11 (30%) of DIP cases (P<.0001). A normal pattern, used as a diagnostic test for DIP, had 70.3% sensitivity (95% confidence interval [CI], 53.0-84.1), 83.9% specificity (95% CI, 71.7-92.4), a 32.7% positive predictive value, and a 97.9% negative predictive value. Of 17 patients with DIP with a normal pattern of 32-2B, 14 recovered, whereas only 2 of 9 patients with DIP with a patchy pattern recovered (P<.005).32-2B immunolabeling is useful for diagnosing DIP and is an indicator of a good prognosis.

Heme oxygenase-1 inducer hemin prevents vascular thrombosis

Hemin is a heme oxygenase-1 (HO-1) inducer which provides endogenous carbon monoxide known for playing roles in cell proliferation, inflammation or aggregation process. The objective of the current study was to examine the effect of prophylactic treatment with hemin in a thrombosis vascular model. Three groups of Wistar rats, control (n = 6), hemin (n = 6) and hemin + HO-1 inhibitor (n = 6), were used for this study. Hemin-treated animals received hemin (50 mg/kg/d; I.P.) for seven days and HO-1 inhibitor group received hemin at the same dose and SnPP IX (60 mg/kg/d; I.P.). All animals were exposed to electric stimulation of the left carotid according to Kawasakis procedure to induce reproducible thrombus formation. The hemin treatment did not induce blood pressure disturbance. Effects of hemin on vascular thrombosis were quantified by histopathology and its influence on haemostasis was assessed by measuring prothrombin time (PT), activated partial thromboplastin time (APTT) and blood parameters at the end of treatment. The HO-1 mRNA and protein level variation were also checked out. Results showed that chronic treatment with hemin significantly (p < 0.01) reduced the vascular occlusion degree when compared to control and hemin SnPP groups with 7.2 +/- 4.6 vs. 71.1 +/- 14.7 and 74.0 +/- 8.8%, respectively. Moreover, we observed significant (p < 0.05) perturbations of blood parameters in hemin-treated and hemin-SnPP treated rats. Interestingly, hemin treatment did not significantly increase both PT and APTT. Finally, the HO-1 mRNA and protein levels were increased in hemin-treated carotid artery. In conclusion, hemin by inducing HO-1 expression may be a preventive agent against clinical disorders associated to an increased risk of thrombosis events and may limit haemorrhagic risks.

Heme Oxygenase-1 Inducer Hemin Attenuates the Progression of Remnant Kidney Model

Backgrounds/Aims: Heme oxygenase-1 (HO-1) has been shown to protect against fibrotic proliferation and apoptosis in several models of renal damage. The purpose of this study was to evaluate the impact of a treatment with the HO-1 inducer hemin on the progression of chronic kidney disease in nephrectomized rats versus the AT1 receptor antagonist losartan. Methods: The rats underwent 5/6 renal ablation and after the procedure received either losartan (20 mg/kg/day; n = 9), hemin (50 mg/kg/twice a week; n = 8) or vehicle (n = 8) over a 12-week period. At week 12, blood pressure was measured, urine, blood and remnant kidney were collected for biochemical (proteinuria, urea, creatinine) and histopathological (degrees of glomerulosclerosis and tubular atrophy) analysis. The expressions of HO-1, bone morphogenic protein 7 (BMP-7) and TGF-β were assessed by immunochemistry, and the level of the apoptosis marker protein caspase-3 by Western blot, on the remnant kidney. Results: Hemin significantly reduced blood pressure, proteinuria, inhibited the expression of TGF-β and caspase-3 protein and increased BMP-7 expression protein. Hemin-treated rats had lower glomerulosclerosis and tubular atrophy indexes than controls. Conclusion: Hemin treatment attenuates the progression of chronic kidney disease and appears more efficient than losartan in our rat model hypothetically because of the impact of hemin on the renal expression of BMP-7.

Supratentorial clear cell ependymomas with branching capillaries demonstrate characteristic clinicopathological features and pathological activation of nuclear factor-kappaB signaling

BACKGROUNDnClear cell ependymoma is one of the 4 main histological subtypes of ependymomas defined by the World Health Organization (WHO) classification of tumors of the CNS. DNA methylation profiling can distinguish 4 subgroups of intracranial ependymomas, including supratentorial (ST) ependymomas with Yes-associated protein 1 fusion (YAP1), ST ependymomas with fusion of v-rel avian reticuloendotheliosis viral oncogene homolog A (RELA), posterior fossa ependymomas with balanced genome, and posterior fossa ependymomas with chromosomal instability. In addition, trisomy 19 is a genomic hallmark of ependymomas with rich branching capillaries. However, the relation of histological and molecular subtypes is unclear.nnnMETHODSnHere, we report a series of 20 ependymomas histologically defined by clear cells and branching capillaries.nnnRESULTSnWe observed a strong male predominance. Median age at surgery was 10.4 years (range, 0.8-68.4). All cases were ST, cortical, contrast enhancing, and most often frontal, cystic, and calcified. All tumors qualified as WHO grade III. Some of them exhibited neuronal differentiation. Trisomy 19 was recorded in 13 cases. All samples strongly accumulated p65RelA protein within nuclei, indicating pathological activation of the nuclear factor-kappaB pathway. We identified causative C11ORF95-RELA fusion in almost all cases. Median progression-free survival and overall survival were 11.4 years (95% CI: 5.1-17.8) and not reached, respectively.nnnCONCLUSIONnST clear cell ependymomas with branching capillaries display characteristic clinicopathological features and are associated with pathological activation of nuclear factor-kappaB signaling, which may indicate a potential novel target for therapy in these patients.

Juvenile xanthogranuloma with hematological dysfunction treated with 2CDA‐AraC

Juvenile xanthogranuloma was diagnosed in two infants aged 8 and 2 months with skin lesions, hepatosplenomegaly, and pancytopenia. Disease control was not achieved with first‐line vinblastine–steroid–VP16 combination therapy. Two courses of 2‐chlorodeoxyadenosine (2CDA) (0.3u2009mg/kg) and cytosine arabinoside (AraC) (1u2009g/m2) were then administered for 5 days and were followed, after hematological recovery, by maintenance therapy. Both patients had normal complete blood cell counts and no signs of JXG, respectively, 31 and 24 months after diagnosis. Pediatr Blood Cancer. 2010;55:757–760.

Short- and Long-Term Cardioprotective Effect of Darbepoetin-α: Role of Bcl-2 Family Proteins

The purpose of this study was to assess the short- and long-term cardioprotective effects of darbepoetin-α (DA) in a rat myocardial ischemia and reperfusion model and to investigate the signaling pathway through which DA limits cardiomyocytes apoptosis. Rats were subjected to 40 minutes of coronary artery ligation followed by 72 hours or 4 weeks reperfusion and received either DA (3 or 30 μg/kg, DA3 and D30 groups) or vehicle (control) prior to ischemia. In the DA groups reperfused for 72 hours, left ventricular shortening fraction and left ventricular ejection fraction were higher than that in the control rats (P < 0.05), in agreement with a smaller left ventricular (LV) infarct size. DA treatment activated the JAK2/Akt signaling pathway, lowered cleaved caspase-3, and increased both phosphorylated-Bad and phosphorylated-GSK-3β proteins. This was consistent with the decrease of reactive oxygen species production and the lowered binding of Bad to Bcl-xL and Bcl-2 in a DA30 group of rats. Similarly, in the DA-4-week group, LV function was greater compared to the control. Histology alterations implicated lower LV cardiac fibrosis and greater capillary density; furthermore, both Bcl-xL and Bcl-2 were upregulated. In conclusion, DA afforded short- and long-term cardioprotective effects. Antiapoptotic effects, through the activation of Akt that regulates the Bcl-2 family proteins and activates GSK-3β, are central in the DA cardioprotective mechanism.

Cutaneous Rosai-Dorfman Disease Located on the Breast: Rapid Effectiveness of Methotrexate After Failure of Topical Corticosteroids, Acitretin and Thalidomide.

An erythematous cutaneous plaque on the breast with no signs of infection requires a skin biopsy to rule out dermal extension of an underlying mammary adenocarcinoma, primary skin tumour (e.g. angiosarcoma or malignant lymphoma) (1), or inflammatory lymphoedema of the breast (2). It can more rarely reveal location on the skin of systemic disease. Rosai-Dorfman disease (RDD), also known as sinus histiocytosis with massive lymphadenopathy, is a benign proliferative disorder of histiocytes first described in 1965 by Destombes on nodal biopsy (3). It was subsequently recognised as a distinct clinicopathologic entity by Rosai & Dorfman (4). Cases of RDD located solely on the skin have rarely been reported, and thus treatment is not well-codified (5). We report a case of RDD on the breast which showed rapid partial response to methotrexate.

Ultrastructural demonstration of a relationship between acquired cutis laxa and monoclonal gammopathy.

Acquired cutis laxa is an uncommon disorder sometimes associated with monoclonal gammopathy and multiple myeloma, although the mechanism of this link is unclear. We report here a case of a 34-year-old man with generalized acquired cutis laxa and monoclonal light chain disease with renal and neurological involvement. Electron microscopy examination of a skin sample revealed shortened and fragmented elastic fibres in the reticular dermis and normal collagen bundles. Immunogold labelling revealed anti-lambda antibodies closely bound to the microfibrillar component of elastic fibres, thus supporting a causal relationship between monoclonal gammopathy and the changes in skin elasticity.