Differential analysis of glioblastoma multiforme proteome by a 2D-DIGE approach.

BACKGROUND: Genomics, transcriptomics and proteomics of glioblastoma multiforme (GBM) have recently emerged as possible tools to discover therapeutic targets and biomarkers for new therapies including immunotherapy. It is well known that macroscopically complete surgical excision, radiotherapy and chemotherapy have therapeutic limitations to improve survival in these patients. In this study, we used a differential proteomic-based technique (2D-Difference Gel Electrophoresis) coupled with matrix-assisted laser desorption/ionization-time of flight (MALDI-TOF) mass spectrometry to identify proteins that may serve as brain tumor antigens in new therapeutic assays. Five samples of patients presenting a GBM and five samples of microscopically normal brain tissues derived from brain epileptic surgery specimen were labeled and run in 2D-PAGE (Two-Dimensional Polyacrylamide Gel Electrophoresis) with an internal pool sample on each gel. Five gels were matched and compared with DIA (Difference In-gel Analysis) software. Differential spots were picked, in-gel digested and peptide mass fingerprints were obtained. RESULTS: From 51 protein-spots significantly up-regulated in GBM samples, mass spectrometry (MS) identified twenty-two proteins. The differential expression of a selected protein set was first validated by western-blotting, then tested on large cohorts of GBM specimens and non-tumor tissues, using immunohistochemistry and real-time RT-PCR. CONCLUSIONS: Our results confirmed the importance of previously described proteins in glioma pathology and their potential usefulness as biological markers but also revealed some new interesting targets for future therapies.

Intradural extramedullary spinal inflammatory myofibroblastic tumor: case report and literature review.

The authors present the case of an inflammatory myofibroblastic tumor that involves the cervical spinal cord meninges, presenting in a manner mimicking en plaque meningioma, which has never been previously reported. During the first surgical procedure, which did not involve exploration of the intradural space, inflammatory epidural tissue was found. We performed a second operation to remove the tumor that was finally intradural, dural-based and very tough. Imaging studies, surgical findings, and histopathological examinations were used to support the diagnosis. Intradural extramedullary inflammatory myofibroblastic tumor is a rare entity that has only been described nine times in the literature. Surgery remains the treatment of choice. Although histologically benign, spinal inflammatory myofibroblastic tumor can be aggressive and requires a large resection and long-term follow-up of the entire central nervous system with magnetic resonance imaging.

Surgical treatment of rare cauda equina tumours.

BACKGROUND: Cauda equina tumours (CET) are rare and usually benign. Treatment of schwannomas and benign ependymomas, which are the most frequent histopathological types of CET, is now well established. However, management of other presumed histopathological types of CET is still a matter of debate. The aim of this study was to assess the incidence and the surgical treatment of rare CET. METHOD: A retrospective study was carried out on 176 adult patients surgically treated for CET in our two departments from 1994 to 2010. We reviewed pre- and postoperative symptoms, magnetic resonance imaging aspects, surgical findings, outcome including operative neurological morbidity, local recurrence rate and operative mortality, and incidence of rare CET. FINDINGS: Seventeen percent (30 patients) of CETs operated on were neither schwannomas nor benign ependymomas. Half of these cases were benign tumours, with paragangliomas being the most common. Two patients were in poorer clinical condition after surgery, one patient experienced a local recurrence, and one died following surgery, from the progress of his disease (Von Hippel-Lindau disease). The other half were malignant tumours, with metastases being the most common. One third of the patients were worsened by surgery, and the mortality rate was 1/3 at 8 months (1-27 months). CONCLUSIONS: Roughly one in six CET were neither schwannomas nor benign ependymomas. This study demonstrated the efficiency of surgery for rare benign CET with a low local recurrence rate. Surgical treatment of rare malignant CET led to a high rate of increased postoperative neurological deficit in patients with a reduced life expectancy.

DNA methylation in glioblastoma: impact on gene expression and clinical outcome.

BACKGROUND: Changes in promoter DNA methylation pattern of genes involved in key biological pathways have been reported in glioblastoma. Genome-wide assessments of DNA methylation levels are now required to decipher the epigenetic events involved in the aggressive phenotype of glioblastoma, and to guide new treatment strategies. RESULTS: We performed a whole-genome integrative analysis of methylation and gene expression profiles in 40 newly diagnosed glioblastoma patients. We also screened for associations between the level of methylation of CpG sites and overall survival in a cohort of 50 patients uniformly treated by surgery, radiotherapy and chemotherapy with concomitant and adjuvant temozolomide (STUPP protocol). The methylation analysis identified 616 CpG sites differentially methylated between glioblastoma and control brain, a quarter of which was differentially expressed in a concordant way. Thirteen of the genes with concordant CpG sites displayed an inverse correlation between promoter methylation and expression level in glioblastomas: B3GNT5, FABP7, ZNF217, BST2, OAS1, SLC13A5, GSTM5, ME1, UBXD3, TSPYL5, FAAH, C7orf13, and C3orf14. Survival analysis identified six CpG sites associated with overall survival. SOX10 promoter methylation status (two CpG sites) stratified patients similarly to MGMT status, but with a higher Area Under the Curve (0.78 vs. 0.71, p-value < 5e-04). The methylation status of the FNDC3B, TBX3, DGKI, and FSD1 promoters identified patients with MGMT-methylated tumors that did not respond to STUPP treatment (p-value < 1e-04). CONCLUSIONS: This study provides the first genome-wide integrative analysis of DNA methylation and gene expression profiles obtained from the same GBM cohort. We also present a methylome-based survival analysis for one of the largest uniformly treated GBM cohort ever studied, for more than 27,000 CpG sites. We have identified genes whose expression may be tightly regulated by epigenetic mechanisms and markers that may guide treatment decisions.

Olfactory ensheathing cell tumour: case report and literature review.

Olfactory ensheathing cell tumour (OECT) and olfactory groove schwannoma (OGS) are among the rarest intracranial tumour types that develop within anterior cranial fossa. These tumours share several similarities, including radiological and histological aspects, and only immunohistochemical staining can differentiate between them. We report a case of OECT occurring in a 28-year-old woman with a history of complex partial seizures, emotional lability and anosmia. Radiological features showed a predominantly left subfrontal extra-axial mass. Total excision of the tumour, connected to the cribriform plate and contiguous to the left olfactory bulb, was performed. Histological examination suggested an atypical schwannoma; however, immunohistochemical staining was strongly positive for S-100 protein but negative for both epithelial membrane antigen (EMA) and CD 57 (Leu-7). The final diagnosis was olfactory ensheathing cell tumour. We describe the third case of OECT and emphasize the important role of immunohistochemical staining in diagnosis: awareness of this entity, and use of immunohistochemistry help to distinguish it from OGS.

Prognostic value of O6-methylguanine-DNA methyltransferase status in glioblastoma patients, assessed by five different methods.

This multicenter study assesses the value of O(6)-methylguanine-DNA methyltransferase (MGMT) status for predicting overall survival in glioblastoma patients. Five methods are used, to identify the approach with the best prognostic value. Eighty-one tumors were obtained from patients with glioblastomas treated by surgery and radiotherapy with concomitant temozolomide (TMZ) followed by adjuvant TMZ. MGMT promoter methylation was assessed by qualitative methyl-specific polymerase chain reaction (MSP), semiquantitative methyl-specific polymerase chain reaction (SQ-MSP), and pyrosequencing, while MGMT expression was measured at the RNA level by quantitative real-time PCR (Q-RT-PCR) and at the protein level by immunohistochemistry (IHC). MGMT promoter methylation as evaluated by MSP, SQ-MSP, and pyrosequencing was significantly correlated with overall survival. The best predictive value was obtained by pyrosequencing of one specific CpG position. Overall survival was 14 and 25 months for patients with percentages of methylation below and above the median, respectively. In contrast, MGMT status determined by Q-RT-PCR and IHC showed little or no correlation with overall survival, respectively. These results confirm the prognostic value of MGMT promoter methylation in glioblastoma patients initially treated with TMZ. SQ-MSP allowed better discrimination than classical MSP, and pyrosequencing represented a good option.

Integrative genome-wide analysis reveals a robust genomic glioblastoma signature associated with copy number driving changes in gene expression.

Glioblastoma multiforme shows multiple chromosomal aberrations, the impact of which on gene expression remains unclear. To investigate this relationship and to identify putative initiating genomic events, we integrated a paired copy number and gene expression survey in glioblastoma using whole human genome arrays. Loci of recurrent copy number alterations were combined with gene expression profiles obtained on the same tumor samples. We identified a set of 406 "cis-acting DNA targeted genes" corresponding to genomic aberrations with direct copy-number-driving changes in gene expression, defined as genes with either significantly concordant or correlated changes in DNA copy number and expression. Functional annotation revealed that these genes participate in key processes of cancer cell biology, providing insights into the genetic mechanisms driving glioblastoma. The robustness of the gene selection was validated on an external microarray data set including 81 glioblastomas and 23 non-neoplastic brain samples. The integration of array CGH and gene expression data highlights a robust cis-acting DNA targeted genes signature that may be critical for glioblastoma progression, with two tumor suppressor genes PCDH9 and STARD13 that could be involved in tumor invasiveness and resistance to etoposide.

Topotecan in combination with radiotherapy in unresectable glioblastoma: a phase 2 study.

Improving glioblastoma multiforme (GBM) treatment with radio-chemotherapy remains a challenge. Topotecan is an attractive option as it exhibits growth inhibition of human glioma as well as brain penetration. The present study assessed the combination of radiotherapy (60 Gy/30 fractions/40 days) and topotecan (0.9 mg/m(2)/day on days 1-5 on weeks 1, 3 and 5) in 50 adults with histologically proven and untreated GBM. The incidence of non-hematological toxicities was low and grade 3-4 hematological toxicities were reported in 20 patients (mainly lymphopenia and neutropenia). Partial response and stabilization rates were 2% and 32%, respectively, with an overall time to progression of 12 weeks. One-year overall survival (OS) rate was 42%, with a median OS of 40 weeks. Topotecan in combination with radiotherapy was well tolerated. However, while response and stabilization concerned one-third of the patients, the study did not show increased benefits in terms of survival in patients with unresectable GBM.

Survival and prognostic factors in a series of adults with medulloblastomas.

OBJECT: In this article, the authors report their experience in the management of adult patients with medulloblastoma at their institution to identify prognostic factors important for survival and disease control. METHODS: Between 1977 and 2005, 27 patients who were >or=16 years old and had medulloblastoma were treated consecutively. There were 16 women and 11 men with a median age of 21 years (range 16-54 years). Gross-total resection was performed in 21 patients, subtotal (>or=90%) in 2, incomplete in 1, and biopsy in 3 patients. Six patients had the desmoplastic variant, and 21 patients presented with classic medulloblastoma. Staging according to the Chang classification showed 4 patients with tumors invading the brainstem (2 with Stage T3b and 2 with Stage T4), 3 patients with metastases (2 with Stage M2 and 1 with Stage M3), and 1 patient in whom the stage was unknown (Stage MX) who died 10 days postoperatively. Twenty patients were assigned to the standard-risk group and 7 to the high-risk group. All patients except the one whose status was classified as Stage MX underwent craniospinal radiotherapy at our institution. Seven patients received chemotherapy before radiotherapy. RESULTS: The 5- and 10-year overall survival rates for the present study were 81 and 62%, respectively. The median overall survival time was 17.7 years. The 5- and 10-year event-free survival rates were 72 and 57%, respectively. The median event-free survival time was 17.9 years. Univariate analysis showed that survival was significantly correlated with sex (women had a better prognosis than men) and M stage (patients without metastases had a better outcome). Patient age, duration of symptoms, Karnofsky Performance Scale score at presentation, hydrocephalus, tumor location, brainstem invasion, extent of resection, histological subtype, preradiotherapy chemotherapy, risk group, and period of presentation were not significant variables. Multivariate analysis identified sex and M stage as well as the period of presentation as independent prognostic factors for overall and event-free survival times. Eleven patients suffered tumor recurrence within a median time of 4.2 years. The posterior fossa was not the most common site of recurrence, and delayed recurrence was not rare. All patients in whom the tumor recurred have died despite aggressive treatments. The median survival time after diagnosis of recurrence was 2.5 years. Questionnaires on quality of life and cognition showed high scores in favor of limited negative effects in the perception of mental and physical health after treatment. The authors observed 1 supposed second malignancy (thyroid carcinoma) and no evidence of pituitary dysfunction. CONCLUSIONS: Long-term survival is possible in adults treated for medulloblastoma. Although rare, metastasis seeding at presentation is a poor prognostic factor. The possibility of delayed recurrence necessitates close follow-up of all patients. Tumor recurrences should be treated with aggressive therapies as some patients may have sustained response. Adjuvant chemotherapy should be given to high-risk patients, but its role in reducing recurrences, particularly distant ones, remains unclear in the standard-risk group.

Hearing loss attributable to a cerebellopontine-angle arachnoid cyst in a child.

Although hearing loss in newborns and infants is predominantly due to malformations and infections, there are other situations which may compromise hearing quality in later stages, including posterior-fossa arachnoid cysts (ACs). We report the case of an 8-year-old girl who presented with hearing loss linked to a pontocerebellar-angle AC which had been diagnosed and treated when she was 14 months old. The pathophysiology of this late AC complication is discussed. This case reminds us that a close follow-up with audiologic monitoring and/or brain stem auditory evoked response is necessary in children with posterior-fossa AC because modern neuroradiological imaging methods do not inform about cerebral and nerve functions, although they provide excellent morphological details of ACs and have improved the ease and accuracy of their early diagnosis. Therefore, surgery should be performed before complete hearing loss occurs; however, in hearing-impaired patients, it remains unclear which surgical treatment is most appropriate.

Cerebellar pleomorphic xanthoastrocytoma: case report and literature review.

BACKGROUND: PXA generally has histologic features characteristic of benign biological behavior, although malignant forms have been reported. This neoplasm has also been observed in atypical locations. METHODS: The authors report a case of cerebellar PXA with rapid malignant transformation in a 58-year-old woman and review the rare presentations and atypical features of this tumor. RESULTS: Among the "unusual" locations, the most frequent is the cerebellum with 15 cases having been described, 9 in adults, with an average age of 33 years. In contrast, supratentorial forms had a younger age profile (26 years). The time from onset of symptoms to diagnosis was approximately 5.3 months. PXA in the posterior fossa had a higher rate of solid enhancing tumor (9/14). Regarding histologic appearance, two thirds were composite lesions. CONCLUSIONS: The clinicopathologic features of cerebellar PXA show some differences from PXA located in the cerebral hemispheres. Recognizing the potential for PXA to present with unusual manifestations, regardless of location, has an obvious impact on the accuracy of diagnosis.

Stem cells adaptive network: mechanism and implications for evolution and disease development.

During development, different cells and tissues acquire different programmes of gene expression, so that cells are related to each other through a somatic cells tree or cluster and adult pluripotential stem cells (PSC) may be defined as progenitors that we distinguish in four types according to their biological behaviour. This clustering may segregate specific pathways establishing spatial patterns of cell-cell communications. Thus, we suggest that normal somatic cells renewal is tributary of multipotential stem cells (MSC), while renewal of cells undergoing stress or abnormal death is tributary of PSC through specific pathway(s) from cluster, thus, defining the cell repertoire that will be produced. We also assume that PSC play a pivotal role in evolutionary and propose the theory of "internal clusters competition". According to the functional duality of stem cells (SC) we define a stem cells adaptive network (SCAN) which we believe is linked to the central clock and display two pathways. The diurnal pathway includes SC-somatic cells communications, while the nocturnal pathway includes inter-SC network. These alternate pathways could be activated or repressed as a consequence of change in the biological chirality. This new approach of SC may contribute to our understanding on how some diseases may develop including cancer which could be linked to "cluster illness", while demyelinating and systemic diseases could be related to "PSC locus illness" or "focalised SCAN disturbances" and it explains how any environment stress may act on organism evolution.

[Surgery for intracranial meningiomas in patients older than 80 years]. / Chirurgie des méningiomes intracrâniens après 80 ans.

OBJECTIVE: To evaluate surgery for intracranial meningiomas in very elderly patients. METHOD: We retrospectively reviewed the clinical, radiological and therapeutic data of patients older than 80 years who underwent surgery for symptomatic intracranial meningioma at our institution between May 1998 and February 2005. We estimated operative mortality and morbidity and patients' functional status at 3 months and one year after surgery as well as at their last clinical evaluation. RESULTS: Eleven patients met these inclusion criteria: 5 men and 6 women, with a mean age of 83 years (range: 81-87 years). There was no perioperative mortality and one patient with perioperative morbidity (hemiplegia). Three months after surgery, the condition of 6 patients had improved, while it had not changed for 4 and had worsened for one. One year after surgery, 5 had improved, 5 were unchanged, and one patient had died. Of the 10 patients alive one year after surgery, 8 had Karnofsky scores> or =80 (self-sufficient). Three patients died more than one year after surgery of causes unrelated to their meningioma. CONCLUSION: Old age does not contraindicate surgery for intracranial meningiomas. Surgery should be proposed for patients older than 80 years with symptomatic intracranial meningioma.

Pathophysiology of glioma cyst formation.

Fluid filled cystic cavities are accompaniments of some cerebral gliomas. These tumoural cysts together with peritumoural vasogenic brain oedema add to the morbid effects of the gliomas in terms of mass effect and increased intracranial pressure. Although different mechanisms have been suggested as to the pathogenesis of glioma-associated cysts, it is still unclear why these cysts appear in only a limited number of cerebral gliomas while brain oedema, a probable precursor of glioma cysts, is a usual accompaniment of most gliomas. Here, the authors present a two-hit hypothesis of brain glioma cyst formation. We suggest that after the formation of vasogenic tumoural brain oedema, microvascular phenomena may lead to the formation of microcysts, which might later become confluent and grow to form macroscopic cysts. Progress in the understanding of pathogenesis of cerebral glioma cysts might set targets for treatment of brain edema and glioma cysts.

Pathophysiology of intracranial epidural haematoma following birth.

Epidural haematoma in newborn infants is rare, and few specific obstetrical data related to its formation are available in the literature. The aim of this study is to discuss the pathophysiology of this condition. EDH is always a post traumatic lesion and it is only possible if the insult has produced a cleavage of the dura mater from bone. Therefore, EDH results from the mechanical forces exerted on the foetal head during birth, with or with no instrumental interference. Although it is still unclear whether the injury (and dura mater cleavage) was directly caused by the forceps or had already been inflicted by natural forces, or a combination of both however, in some patients (with neither dystocia nor skull fracture), there is no basis for explaining EDH formation, apart from propulsion of the fore coming head through the birth canal. Excessive moulding, whether or not associated with iatrogenic trauma, has been incriminated in most cases of EDH. As dystocia cannot always be anticipated, EDH will remain an ever-present cause of morbidity in the neonatal population, albeit a rare occurrence.

Theoretical considerations on the pathophysiology of normal pressure hydrocephalus (NPH) and NPH-related dementia.

Normal pressure hydrocephalus (NPH) is considered to be an example of reversible dementia although clinical improvement after shunting varies from subject to subject, and recent studies have pointed to a possible link with other dementia. The authors consider that the craniospinal compartment is a partially closed sphere with control device systems represented by the spinal axis and the sagittal sinus-arachnoid villi complex which interact with each other in the clinical patient setting. We hypothesise that changing spinal compliance by altering the flow process and CSF dynamics lead to hydrocephalus. Therefore four NPH types have been distinguished according to the alterations in spinal compliance, decrease in CSF absorption at the sagittal sinus or both occurrences. The authors consider that NPH and NPH-related diseases (NPH-RD) are initiated by the same common final pathway and demonstrate that NPH could represent an initial stage of NPH-RD. Progression of clinical signs can be explained as damage to the cerebral tissue by both intermittent increased intracranial pressure and pulse pressure waves leading to periventricular ischaemia. In addition, they believe that both volume equilibrium and spinal compliance are restored in patients who improve after CSF shunt, whereas in patients whose condition does not improve, only volume equilibrium is restored and not spinal compliance, which was the underlying cause of hydrocephalus in such cases. They therefore wonder whether cervical decompression should not be indicated in patients who show no improvement. Although attractive, this analysis warrants confirmation from clinical, radiological, and hydrodynamic studies.

Idiopathic normal pressure hydrocephalus: theoretical concept of a spinal etiology.

Normal pressure hydrocephalus (NPH) is an adult syndrome characterised by a combination of gait disturbance, varying degrees of cognitive decline, urinary incontinence, ventricular enlargement and normal mean intracranial pressure. Since this syndrome was first described, its pathophysiology has been a matter of great debate, although it is now considered that NPH could be divided into two groups: cases with unknown etiology (idiopathic normal pressure hydrocephalus, or INPH) and those which develop from several known causes (such as trauma, meningitis or subarachnoid haemorrhage). The pathophysiology of INPH is still unclear and a matter of debate. In this manuscript, the current pathophysiological conditions of INPH are analysed and the authors put forward the theory that the disease is a dynamic syndrome which occurs in patients who have suffered a significant loss of spinal compliance over time. Consequently, intracranial pressure increases more during systole in INPH patients because it cannot be compensated for by the escape of CSF into the spinal canal as effectively, due to the reduced volume or lack of distension of the spinal canal. This leads to an increase in ventricular size and causes cumulative brain damage over a long period of time and accounts for the slow, progressive nature of NPH. The loss of spinal compliance with age is fundamental to the proposed theory which provides a theoretical justification for studying the spinal canal in INPH and investigating the relationship between the progressive narrowing of the spinal canal and the compensating ability of the craniospinal system.

Incidence and Mortality of Spontaneous Subarachnoid Hemorrhage in Martinique.

BACKGROUND: Incidence of spontaneous subarachnoid hemorrhages (SAH) varies wildly across the world and seems to be low in Central and South America (4.2 per 100 000 person-years; CI 95%; 3.1-5.7). The objective of our study was to describe the characteristics of SAH and to estimate its incidence and severity in Martinique, a small French island located in the Caribbean Sea. METHODS: Due to its insular nature and small captive population, Martinique is ideal for the setting up of population-based epidemiological studies with good exhaustiveness. Our study, spanning a 7 year period (2007-2013), consisted of retrospective case ascertainment with multiple overlapping methods. Crude incidence and 30 day case-fatality rates for SAH among the Martinican population were computed for the study period. Incidence and disease severity was also analyzed according to age, gender and aneurysm presence. World age-standardized incidence rates were also calculated. RESULTS: A total of 121 patients had a SAH during the study period, with a higher frequency of female cases (71.1% versus 28.9%, p<0.001). Patient mean age was 57.1 years (median = 55 [46-66]). An aneurysmal origin was found in 96 SAH cases (79.3%). Crude annual incidence was 4.36 per 100 000 person-years (CI 95% 2.30-6.42). World age-standardized incidence was 3.29 per 100 000 person-years (CI 95% 1.74-4.84). During the 30 days following SAH diagnosis, 29 patients died (case fatality rate: 24% (CI 95% 16.4-31.6)). CONCLUSIONS: The incidence of spontaneous subarachnoid hemorrhage in Martinique is much lower than in other parts of the world and similar to countries in Central and South America. These results are possibly related to environmental factors and most particularly to a low rate of smoking in the Martinican population. Thirty-day case-fatality rate is similar to what is observed in developed countries.

Multicentric pleomorphic xanthoastrocytoma in a patient with neurofibromatosis type 1. Case report and review of the literature.

The authors report an unusual case of multicentric pleomorphic xanthoastrocytoma (PXA) in a 36-year-old woman with neurofibromatosis Type 1 (NF1). Both lesions were diagnosed as PXA but demonstrated different neuroimaging features and very different outcomes. Although the occipital lesion was cured surgically, the cerebellar tumor recurred three times and underwent malignant transformation into an anaplastic oligodendroglioma. The authors discuss the causes of PXA and suggest that it could originate from common bipotential precursor cells with two phenotypes.

Pathophysiology of capillary haemangioma growth after birth.

Capillary haemangiomas (CHs) are the most common soft tissue tumours of infancy. It is generally believed that the primary defect in CHs is intrinsic to endothelial cells, but their pathogenesis is yet poorly understood. The relatively low oxygen environment, in which the human foeto-placental unit develops, during the first trimester, is necessary to induce vasculo-angiogenesis via embryonic endothelial cells proliferation, since these cells are sensitive to hypoxia and acidosis. In newborn infants with haemangioma, persistent embryonic primitive endothelial cells trapped in the intimae underneath the developing vessels, and representing "leader" endothelial cells, can stabilise the labile vascular endothelial growth factor mRNA (VEGF mRNA), produce other angiogenic factors, degrade the underlying basement membrane and invade into the stroma of the neighbouring tissue. With bearing down, the transition from intra- to extra-uterine life is accompanied by more or less pronounced hypoxia. Consequently, in babies with haemangioma, hypoxia can act as a switch to activate these "leader" endothelial cells and thereby initiate a cascade of reactions leading to CH proliferation. As they are regulated by embryonic cells, the haemangioma growth mechanisms pursue the pathway of embryonic angiogenesis and it will stop at the end of the embryonic endothelial cell cycle. Addressing this mechanism in vivo has partly been done (the angiogenic peptide bFGF varies with haemangioma growth). Thus, early treatment seems necessary in infants with haemangioma, before the endothelial cells achieve their proliferative stage. The use of an antibody to interfere with VEGF receptors provides a particular attractive strategy.