Romain Vanwijck

Tumor regressions observed in patients with metastatic melanoma treated with an antigenic peptide encoded by gene MAGE-3 and presented by HLA-A1.

Thirty‐nine tumor‐bearing patients with metastatic melanoma were treated with 3 subcutaneous injections of the MAGE‐3.A1 peptide at monthly intervals. No significant toxicity was observed. Of the 25 patients who received the complete treatment, 7 displayed significant tumor regressions. All but one of these regressions involved cutaneous metastases. Three regressions were complete and 2 of these led to a disease‐free state, which persisted for more than 2 years after the beginning of treatment. No evidence for a cytolytic T lymphocyte (CTL) response was found in the blood of the 4 patients who were analyzed, including 2 who displayed complete tumor regression. Our results suggest that injection of the MAGE‐3.A1 peptide induced tumor regression in a significant number of the patients, even though no massive CTL response was produced. Int. J. Cancer 80:219–230, 1999.

Capillary malformation-arteriovenous malformation, a new clinical and genetic disorder caused by RASA1 mutations.

Capillary malformation (CM), or port-wine stain, is a common cutaneous vascular anomaly that initially appears as a red macular stain that darkens over years. CM also occurs in several combined vascular anomalies that exhibit hypertrophy, such as Sturge-Weber syndrome, Klippel-Trenaunay syndrome, and Parkes Weber syndrome. Occasional familial segregation of CM suggests that there is genetic susceptibility, underscored by the identification of a large locus, CMC1, on chromosome 5q. We used genetic fine mapping with polymorphic markers to reduce the size of the CMC1 locus. A positional candidate gene, RASA1, encoding p120-RasGAP, was screened for mutations in 17 families. Heterozygous inactivating RASA1 mutations were detected in six families manifesting atypical CMs that were multiple, small, round to oval in shape, and pinkish red in color. In addition to CM, either arteriovenous malformation, arteriovenous fistula, or Parkes Weber syndrome was documented in all the families with a mutation. We named this newly identified association caused by RASA1 mutations CM-AVM, for capillary malformation-arteriovenous malformation. The phenotypic variability can be explained by the involvement of p120-RasGAP in signaling for various growth factor receptors that control proliferation, migration, and survival of several cell types, including vascular endothelial cells.

Association of Localized Intravascular Coagulopathy With Venous Malformations

OBJECTIVEnTo determine which venous malformations (VMs) are at risk for coagulopathy. Venous malformations are slow-flow vascular malformations present at birth, and localized intravascular coagulopathy (LIC) causes pain and thrombosis within a lesion and severe bleeding during surgical procedures.nnnDESIGNnProspective convenience sample accrued from 2 multidisciplinary sites in Brussels, Belgium, and Caen, France.nnnPARTICIPANTSnThe study population comprised 140 patients with clinical data and coagulation parameters. Magnetic resonance imaging was performed for 110 patients.nnnMAIN OUTCOME MEASUREnMeasurement of D-dimer levels.nnnRESULTSnOf the 140 participants, 59 (42%) showed high D-dimer levels, 36 (61%) of whom had levels higher than 1.0 microg/mL. Six of the participants had low fibrinogen levels. In univariate analysis, large surface, presence of palpable phleboliths, and truncal localization were associated with high D-dimer levels. In the multivariate analysis, only large surface area and presence of phleboliths remained independently associated with high D-dimer levels. Severe LIC, characterized by concomitant low fibrinogen level, was associated with extensive venous malformations of the extremities.nnnCONCLUSIONSnLocalized intravascular coagulopathy is statistically significantly associated with large and/or deep venous malformations that affect any location, which can have a palpable phlebolith. These patients are at risk of local pain due to thrombosis. Lesions with elevated D-dimer levels associated with low fibrinogen levels (severe LIC) commonly affect an extremity and have a high risk of hemorrhage. Low-molecular-weight heparin can be used both to treat the pain caused by LIC and to prevent decompensation of severe LIC to disseminated intravascular coagulopathy.

Ethanol sclerotherapy of venous malformations: evaluation of systemic ethanol contamination.

PURPOSEnTo evaluate blood ethanol concentrations immediately after percutaneous ethanol sclerotherapy of venous malformations (VMs).nnnMATERIALS AND METHODSnThirty consecutive sclerotherapy procedures were performed for VMs in various anatomic sites. In a prospective study, the blood parameters monitored were ethanol plasma level (immediately after the procedure), plasma haptoglobin (Hp; before and after the procedure), and standard blood analysis including urea, creatinine, bilirubin, and lactic dehydrogenase (LDH) levels during the hospital stay.nnnRESULTSnThe mean amount of 94% ethanol injected was 19.7 mL (0.03-0.78 g/kg of body weight). The observed systemic ethanol levels ranged from 0 to 1.16 g/L (mean, 0.33 g/L, SD = 0.33). The relationship between the observed plasmatic ethanol level (ETOH plasma) measured immediately after the procedure and the maximum expected plasmatic ethanol amount (ETOH max) was linear and significant (correlation coefficient r = 0.91 for all lesions, r = 0.96 for lesions without visible venous drainage, r = 0.86 for lesions with visible draining veins, and r = 0.93 for lobulated VMs). Minimal changes were observed for indicators of hemolysis: macroscopic hemoglobinuria in five of 30, abnormal Hp level in seven of 30, and increase in LDH and increase in bilirubinemia in one case each.nnnCONCLUSIONSnSystemic ethanol contamination during sclerotherapy of VMs could be detected in 25 of 30 cases (83.3%). The plasmatic ethanol level was directly proportional to the amount of ethanol injected and not dependent on the VM morphology, venous drainage, or injection technique. Clinicians and interventional radiologists must be aware of this massive ethanol outflow during percutaneous sclerotherapy of VMs and its potentially serious systemic complications.

Interferon regulatory factor-6: a gene predisposing to isolated cleft lip with or without cleft palate in the Belgian population.

Cleft lip with or without cleft palate is the most frequent craniofacial malformation in humans (∼1/700). Its etiology is multifactorial; some are a result of a genetic mutation, while others may be due to environmental factors, with genetic predisposition playing an important role. The prevalence varies widely between populations and the mode of inheritance remains controversial. The interferon regulatory factor-6 (IRF6) gene has been shown to harbor mutations in patients with van der Woude syndrome, a dominant form of clefts associated with small pits of the lower lip. Moreover IRF6 has been associated with nonsyndromic cleft of the palate (CL/P) in two separate studies. We investigated the role of IRF6 in a set of 195 trios from Belgium. Cleft occurred as an isolated feature. We studied association of the IRF6 locus using two variants: one in the IRF6 gene and the other 100u2009kpb 3′ of the gene. Our independent study group confirms that the IRF6 locus is associated with nonsyndromic cleft lip with or without palate. This result, with previous studies performed in the United States and Italy, shows for the first time the implication of IRF6 in isolated CL/P in northern Europe. It is likely that association to this locus can be identified in various populations and that the IRF6 locus thus represents an important genetic modifier for this multifactorial malformation.

FAF1, a Gene that Is Disrupted in Cleft Palate and Has Conserved Function in Zebrafish

Cranial neural crest (CNC) is a multipotent migratory cell population that gives rise to most of the craniofacial bones. An intricate network mediates CNC formation, epithelial-mesenchymal transition, migration along distinct paths, and differentiation. Errors in these processes lead to craniofacial abnormalities, including cleft lip and palate. Clefts are the most common congenital craniofacial defects. Patients have complications with feeding, speech, hearing, and dental and psychological development. Affected by both genetic predisposition and environmental factors, the complex etiology of clefts remains largely unknown. Here we show that Fas-associated factor-1 (FAF1) is disrupted and that its expression is decreased in a Pierre Robin family with an inherited translocation. Furthermore, the locus is strongly associated with cleft palate and shows an increased relative risk. Expression studies show that faf1 is highly expressed in zebrafish cartilages during embryogenesis. Knockdown of zebrafish faf1 leads to pharyngeal cartilage defects and jaw abnormality as a result of a failure of CNC to differentiate into and express cartilage-specific markers, such as sox9a and col2a1. Administration of faf1 mRNA rescues this phenotype. Our findings therefore identify FAF1 as a regulator of CNC differentiation and show that it predisposes humans to cleft palate and is necessary for lower jaw development in zebrafish.

Immediate skin grafting of sub-acute and chronic wounds debrided by hydrosurgery *

A wound bed may be prepared by various non-surgical debridements using autolytic, biological or enzymatic techniques. These are all effective in selective wounds but tend to be time consuming. Surgical debridement is not selective since healthy collateral tissue is also removed. Physical debridement uses whirlpool therapy to slough off necrotic tissues - the saline which comes out of the hand piece if vapourized over the wound - and therefore disseminates contaminated droplets. Hydrosurgery combines physical and surgical debridement but does not have their drawbacks. Water dissection works by using a high-pressure jet of sterile saline that travels parallel to the wound and creates a Venturi effect, thus enabling the selective removal of necrotic tissues without dissemination of contaminants. In this study, the authors report on 167 sub-acute and chronic wounds from 155 patients treated under general anaesthesia by hydrosurgery (Versajet). Of these, 95% of the debrided wounds were immediately covered with an autologous meshed graft. Compared to other debridement techniques, hydrosurgery has two main advantages: namely its tissue selectivity and its high percentage of successful engraftment after immediate skin grafting.

The posterior interosseous nerve and the radial tunnel syndrome: an anatomical study.

Summary. Twenty anatomical specimens were carefully studied in order to establish a possible connection between the posterior interosseous nerve and the radial tunnel syndrome. Our results show that the posterior interosseous nerve distal to the supinator muscle may be compressed by various structures. These include the distal border of the supinator muscle, the ramifications of the anterior and posterior interosseous vessels, and the septum between the extensor carpi ulnaris and the extensor digitorum minimi. The posterior interosseous nerve is also stressed during passive supination (elongation and rotation), and during passive pronation (compression). This suggests that the interosseous nerve distal to the supinator muscle should be explored in radial tunnel compression syndromes.Résumé. Les auteurs ont étudié 20 spécimens anatomiques pour rechercher les liens entre le nerf interosseux postérieur et le syndrome du tunnel radial. L’étude montre que le nerf interosseux postérieur peut être comprimé par diverses structures au-delà du muscle court supinateur: le bord inférieur du court supinateur, les ramifications des vaisseaux interosseux antérieurs et postérieurs et le septum existant entre le cubital postérieur et l’extenseur propre du 5èmee doigt. Le nerf interosseux postérieur est de plus soumi à des strictions lors de la supination passive (élongation et rotation) et lors de la pronation passive (compression). Ceci suggère que le nerf interosseux postérieur doit être exploré dans sa portion distale au-delà du court supinateur lors du traitement des syndromes du tunnel radial.

Pseudo-tumoral proliferative nodule in a giant congenital naevus.

OBJECTIVEnTo discuss the characteristics of proliferative nodules in giant congenital naevi.nnnMETHODSnWe report the case of a newborn referred for staged curettage of a giant congenital naevus. A nodule was discovered on his left flank. It was excised for analysis during the first treatment session during the second week of life.nnnRESULTSnThe nodule was soft and looked like a lipoma. On optical microscopy however, there was a high cellular density and a high number of mitoses. Although the genetic analysis for melanoma antigens was reassuring, a firm nodule recurred a few days later. A second excision was performed at the fourth week. Surprisingly, on optical microscopy, the cellular density was much lower and there were no more atypias or mitoses; many neurotization foci were present. The natural history changed to spontaneous regression of the cellular activity. The diagnosis of proliferative nodule was made.nnnCONCLUSIONnProliferative nodules in giant congenital naevi have specific clinical and histological characteristics. These should however be put into perspective. As demonstrated in this case, there can be an initial high mitotic activity within the nodule but this should not lead to the misdiagnosis of malignant melanoma. The spontaneous regression of cellular activity will allow the correct diagnosis to be made.

A peri-implant capsule flap

Spherical expanders (30 ml) were implanted under the skin vascularised by the left inferior epigastric pedicle in rats. When expansion was complete, the expander was removed and the animals divided into three groups of 15. In the first group, the floor of the capsule was simply everted. In the second group, a capsule island flap was raised; in the third group, a capsule free flap was raised, transferred to the heterolateral vessels by microanastomosis; the inner side of the various capsule flaps was covered with autologous skin graft. In the three experimental groups, there was complete take of the skin grafts in 80% of the animals. Pedicle or free flaps of capsular tissue may be raised and transferred safely in rats.