L. Deschamps

Which magnetic resonance imaging findings accurately evaluate inflammation in small bowel Crohn's disease? A retrospective comparison with surgical pathologic analysis.

Background: The aim was to evaluate the value of magnetic resonance imaging (MRI) findings in Crohns disease (CD) in correlation with pathological inflammatory score using surgical pathology analysis as a reference method. Methods: CD patients who were to undergo bowel resection surgery underwent MR enterography before surgery. The CD pathological inflammatory score of the surgical specimens was classified into three grades: mild or nonactive CD, moderately active CD, and severely active CD; fibrosis was also classified into three grades: mild, moderate, and severe. Mural and extramural MRI findings were correlated with pathological inflammatory and fibrosis grades. Results: Fifty‐three consecutive patients were included retrospectively. The mean delay between MRI and surgery was 24 days (range 1–90, median 14). The CD pathological inflammatory score was graded as follows: grade 0 (11 patients, 21%), grade 1 (15 patients, 28%), and grade 2 (27 patients, 51%). MRI findings significantly associated with pathological inflammatory grading were wall thickness (P < 0.0001), degree of wall enhancement on delayed phase (P < 0.0001), pattern of enhancement on both parenchymatous (P = 0.02), and delayed phase, (P = 0.008), T2 relative hypersignal wall (P < 0.0001), blurred wall enhancement (P = 0.018), comb sign (P = 0.004), fistula (P < 0.0001), and abscess (P = 0.049). The inflammation score correlated with the fibrosis score (r = 0.63, P = 0.0001). Conclusions: Our study identified MRI findings significantly associated with surgical pathological inflammation. These lesions are considered potentially reversible and may be efficiently treated medically. We also showed that fibrosis was closely and positively related to inflammation. Inflamm Bowel Dis 2011

Mature Cytotoxic CD56bright/CD16+ Natural Killer Cells Can Infiltrate Lymph Nodes Adjacent to Metastatic Melanoma

Melanomas are characterized by high metastatic potential, with regional lymph node representing the most frequent site of early dissemination in this disease. These regional lymph nodes also represent the primary site for differentiation of natural killer (NK) cells. Although blood-derived NK cells can efficiently lyse melanoma cells isolated from metastatic lymph node (M-LN), there has been no study of the properties of the most disease-relevant NK cells isolated from M-LN in patients with melanoma. Here, we report that M-LN contains 0.5% to 11% of CD56(bright) NK cells among CD45(+) hematopoietic cells present and that this cell population surrounds tumor cell clusters in M-LN. This NK cell population was characterized by expression of CD62L, chemokine receptors, and high levels of natural cytotoxicity receptors (NCR), NK group 2 D (NKG2D), and DNAX accessory molecule 1 (DNAM-1). Expression of NCR-NKp30 and NKG2D correlated negatively with percentages of tumor cells in M-LN. Interestingly, M-LN contained a unique subset of mature CD56(bright)CD16(+) NK cells displaying coregulated expression of NCR and NKG2D activating receptors. Ex vivo analyses suggested that M-LN-derived NK cells were inactive but could be activated by appropriate cytokine signals [interleukin (IL)-2 or IL-15], and could lyse metastatic melanoma cells in a highly efficient manner compared with blood-derived NK cells. Taken together, the results offer evidence that adjuvant immunotherapy that targets NK cells in M-LN for activation may improve treatment of patients with sentinel lymph node-positive melanoma.

PARKIN Inactivation Links Parkinson’s Disease to Melanoma

BACKGROUND Melanoma incidence is higher in patients affected by Parkinsons disease (PD) and vice versa, but the genetic link shared by both diseases is unknown. As PARK2 is both a tumor suppressor gene and frequently mutated in young onset PD, we evaluated the role of PARK2 in melanoma predisposition and progression. METHODS An in-depth PARK2 gene dosage analysis and sequencing was performed on 512 French case patients and 562 healthy control patients, as well as sporadic tumors and melanoma cell lines. The frequency of genetic alterations was compared between case patients and control patients using two-sided Fishers exact tests and odds ratio (OR) calculations. We used western blotting to determine PARKIN expression in melanocytes and melanoma cell lines and transfection followed by clonogenic assays to evaluate the effect of PARKIN expression on cellular proliferation. All statistical tests were two-sided. RESULTS Germline PARK2 mutations (including copy number variations, splicing, and putative deleterious missense mutations) were present in 25 case patients but only four control patients (OR = 3.95, 95% confidence interval = 1.34 to 15.75). Copy number variations (CNVs) and loss of heterozygosity were present in 60% and 74%, respectively, of primary tumors. PARKIN protein was expressed in melanocytes but not in most melanoma cell lines, and its expression decreased following melanocyte transformation by oncogenic NRAS. Re-expression of PARKIN in melanoma cell lines resulted in a drastic reduction of cell proliferation and inhibition of PARKIN in melanocytes stimulated their proliferation. CONCLUSION Our results show an important role for PARK2 as a tumor suppressor both in melanoma predisposition and progression, which could explain the epidemiological association of these diseases.

Topical Mineralocorticoid Receptor Blockade Limits Glucocorticoid-Induced Epidermal Atrophy in Human Skin

A major deleterious side effect of glucocorticoids is skin atrophy. Glucocorticoids activate the glucocorticoid and the mineralocorticoid (MR) receptor, both present in the epidermis. We hypothesized that glucocorticoid-induced epidermal atrophy may be related to inappropriate occupancy of MR by glucocorticoids. We evaluated whether epidermal atrophy induced by the topical glucocorticoid clobetasol could be limited by coadministration of MR antagonist. In cultured human skin explants, the epidermal atrophy induced by clobetasol was significantly limited by MR antagonism (canrenoate and eplerenone). Blockade of the epithelial sodium channel ENaC by phenamil was also efficient, identifying a role of MR-ENaC cascade in keratinocytes, acting through restoration of clobetasol-induced impairment of keratinocyte proliferation. In the SPIREPI randomized double-blind controlled trial, gels containing clobetasol, the MR antagonist spironolactone, both agents, or placebo were applied on four zones of the forearms of 23 healthy volunteers for 28 days. Primary outcome was histological thickness of the epidermis with clobetasol alone or clobetasol+spironolactone. Spironolactone alone did not affect the epidermal thickness but coapplication of clobetasol and spironolactone significantly limited clobetasol-induced atrophy and was well tolerated. Altogether, these findings identify MR as a factor regulating epidermal homeostasis and suggest that topical MR blockade could limit glucocorticoid-induced epidermal atrophy.

Successful Endovascular Stroke Rescue With Retrieval of an Embolized Calcium Fragment After Transcatheter Aortic Valve Replacement

A 90-year-old symptomatic woman with a critical aortic stenosis was referred for transcatheter aortic valve replacement (TAVR). The procedure was performed under locoregional anesthesia from a right femoral approach, with the successful implantation of a 23-mm CoreValve (Medtronic Inc, Minneapolis, MN). Echocardiographic assessment after TAVR showed a mean transprosthetic gradient of 16 mm Hg and trace paravalvular regurgitation. After percutaneous closure of the right femoral artery, the patient suddenly became unresponsive. After prompt intubation, emergency cerebral MRI was performed to assess the presence of reversible ischemia and exclude parenchymal hemorrhage, showing partial occlusion of the right middle cerebral artery with ischemia in the corresponding territory (Figure 1). Conventional cerebral angiography confirmed partial M1-M2 occlusion of the right middle cerebral artery (Figure 2A; Movie I in the Data Supplement). Complete revascularization …

Characterization of the Microenvironment in Positive and Negative Sentinel Lymph Nodes from Melanoma Patients.

Melanomas are aggressive skin tumors characterized by high metastatic potential. Our previous results indicate that Natural Killer (NK) cells may control growth of melanoma. The main defect of blood NK cells was a decreased expression of activating NCR1/NKp46 receptor and a positive correlation of NKp46 expression with disease outcome in stage IV melanoma patients was found. In addition, in stage III melanoma patients, we identified a new subset of mature NK cells in macro-metastatic Lymph nodes (LN). In the present studies, we evaluated the numbers of NK cells infiltrating primary cutaneous melanoma and analyzed immune cell subsets in a series of sentinel lymph nodes (SLN). First, we show that NKp46+ NK cells infiltrate primary cutaneous melanoma. Their numbers were related to age of patients and not to Breslow thickness. Then, a series of patients with tumor-negative or -positive sentinel lymph nodes matched for Breslow thickness of the cutaneous melanoma was constituted. We investigated the distribution of macrophages (CD68), endothelial cells, NK cells, granzyme B positive (GrzB+) cells and CD8+ T cells in the SLN. Negative SLN (SLN-) were characterized by frequent adipose involution and follicular hyperplasia compared to positive SLN (SLN+). High densities of macrophages and endothelial cells (CD34), prominent in SLN+, infiltrate SLN and may reflect a tumor favorable microenvironment. Few but similar numbers of NK and GrzB+ cells were found in SLN- and SLN+: NK cells and GrzB+ cells were not correlated. Numerous CD8+ T cells infiltrated SLN with a trend for higher numbers in SLN-. Moreover, CD8+ T cells and GrzB+ cells correlated in SLN- not in SLN+. We also observed that the numbers of CD8+ T cells negatively correlated with endothelial cells in SLN-. The numbers of NK, GrzB+ or CD8+ T cells had no significant impact on overall survival. However, we found that the 5 year-relapse rate was higher in SLN with higher numbers of NK cells.

Retrospective Multicentric Study of 25 Kimura Disease Patients: Emphasis on Therapeutics and Shared Features with Cutaneous IgG4-Related Disease

Background: Kimura disease (KD) is a rare lymphoproliferative inflammatory disease of unknown etiology. Data regarding therapeutic modalities and pathophysiology are scarce. Objectives: Analyze therapeutic and follow-up data and compare KD with cutaneous IgG4-related disease (IgG4-RD). Methods: Multicentric retrospective study of 25 KD patients with analysis of treatment, follow-up and IgG4 immunostaining. Comparison with published cases of cutaneous IgG4-RD. Results: Patients were mostly male (84%), median-aged 42 years with lymph node, lacrimal/salivary gland and kidney involvements in 45, 24 and 12%, respectively. Surgical excision had 100% complete response and 60% relapse. Oral corticosteroids had 100% response with 50% relapse. Thalidomide, cyclosporine or interferon-α had 100% response, but 100, 20 and 50% relapse, respectively. KD showed clinicopathological similarities with 27 published cases of cutaneous IgG4-RD. Conclusion: Surgery may be used in resectable KD cases, whereas cyclosporine or thalidomide may represent interesting alternatives to oral corticosteroids in other cases. KD shares features with cutaneous IgG4-RD.

Sézary syndrome without erythroderma

BACKGROUND Sézary syndrome is a cutaneous T-cell lymphoma characterized by erythroderma and leukemic involvement. OBJECTIVE We sought to define the clinical, biologic, and histopathologic features of Sézary syndrome without erythroderma. METHODS Features of patients with Sézary syndrome and normal-appearing skin or stage-T1 patches, fulfilling Sézary syndrome hematologic criteria and with histologically documented disease in normal-appearing skin were collected. Expression of Sézary syndrome molecular biomarkers in peripheral blood and skin lymphocytes were studied. RESULTS Five women and 1 man (median age: 71 years) were all referred for generalized pruritus. Four had no specific lesions; 2 had T1-stage patches. Histologic examination of normal-appearing skin from all patients showed lesions compatible with Sézary syndrome. Peripheral blood lymphocytes from 3 of 4 patients tested strongly expressed PLS3, Twist-1, and KIR3DL2. All normal-appearing skin biopsy specimens expressed programmed death-1. Median follow-up was 9 years. Although no patient developed erythroderma, tumors, or abnormal lymph nodes, specific skin lesions appeared in all patients during follow-up. Only 1 death, unrelated to Sézary syndrome, occurred. LIMITATIONS Retrospective design and small sample size are limitations. CONCLUSION Sézary syndrome without erythroderma is a rare entity that may have a better prognosis than classic Sézary syndrome.

Peeling skin syndrome acral révélé et aggravé par des bolus de méthylprednisolone

Introduction Le peeling skin syndrome acral (PSSA) est une forme clinique du syndrome de desquamation continue, genodermatose cliniquement et genetiquement heterogene caracterisee par un manque de cohesion des cellules de la couche cornee, aboutissant a une desquamation superficielle spontanee ou suite a des traumatismes minimes. Nous rapportons un cas de PSSA aggrave et decouvert a l’occasion de plusieurs bolus de methylprednisolone. Observations Un patient transplante pulmonaire pour une fibrose pulmonaire sur asbestose presentait brutalement un decollement superficiel palmo-plantaire asymptomatique dans les suites d’une perfusion de methylprednislolone pour un rejet aigu. Les diagnostics de toxidermie ou d’eruption scarlatiniforme etaient discutes par le medecin traitant. En interrogeant le patient, qui etait apyretique et ne presentait aucune autre manifestation clinique, il signalait depuis l’enfance des episodes de desquamation limitee au niveau des talons en cas de frottement important. Son frere et un petit fils presentaient la meme symptomatologie jusque la non etiquetee. Il n’y avait pas chez ce patient originaire du Maghreb de consanguinite familiale connue. L’examen clinique revelait une desquamation en lambeaux tres superficiels laissant rapidement place a une peau saine au niveau des paumes et plantes. Cette desquamation etait transitoire et se renouvelait lors des bolus mensuels suivants. L’histologie cutanee mettait en evidence un clivage caracteristique situe sur la moitie superieure de la couche cornee. L’etude ultrastructurale en microscopie electronique objectivait un clivage inter-corneocytaire debutant, avec des tonofilaments un peu desorganises. Discussion Le PSSA est une genodermatose a mode transmission autosomique recessif debutant a la naissance ou dans les premieres annees de vie, associee a des mutations du gene de la transglutaminase 5 et du gene codant pour la cystatine A. L’etude genetique est en cours chez le patient et un membre de sa famille. Les lesions sont classiquement aggravees par la chaleur, l’humidite et la friction. L’aggravation spectaculaire observee suite a un bolus de corticoides n’est pas decrite. In vitro les corticoides rajoutes au milieu de culture de keratinocytes augmentent leur differenciation terminale. Il est probable que les corticoides administres a fortes doses augmentent transitoirement le passage des keratinocytes aux corneocytes revelant le phenotype de peeling syndrome. Conclusion Cette observation de revelation d’un peeling syndrome acral a l’occasion de bolus de methylprednisolone est originale. Paradoxalement l’utilisation prolongee de dermocorticoide permet de controler la symptomatologie vraisemblablement par un effet antiproliferatif sur les keratinocytes.