Laurent Riffaud

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

BackgroundChanges 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.ResultsWe 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).ConclusionsThis 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.

Nevoid basal cell carcinoma syndrome: relation with desmoplastic medulloblastoma in infancy. A population-based study and review of the literature.

Patients with nevoid basal cell carcinoma syndrome (NBCCS) are believed to be predisposed to develop early‐onset neoplasms including medulloblastomas (MB). The desmoplastic subtype of MB is associated most commonly with NBCCS. The goals of this study were to demonstrate the relation between desmoplastic MB and NBCCS and to evaluate the concomitant diagnosis of NBCCS and MB.

Acute nontraumatic spinal subdural hematomas in three patients.

Study Design. The clinical data, magnetic resonance imaging, intraoperative findings, and functional outcome were reviewed for three patients under anticoagulant therapy who experienced acute nontraumatic spinal subdural hematoma. Objectives. To draw attention to this rare complication of anticoagulant therapy and to assess the magnetic resonance findings and clinical outcome of patients with spinal subdural hematoma after surgical evacuation. Summary of Background Data. Among intraspinal hematomas, spinal subdural hematomas are by far the least common. Magnetic resonance findings have been demonstrated in only a few cases of spinal subdural hematomas. The timing of the operation and the anatomic location of the hematoma essentially determine the functional outcome. Methods. Three case reports of spinal subdural hematomas in patients receiving anticoagulant therapy are presented. Particular interest was given to the clinical and magnetic resonance data, the intraoperative findings, and the functional outcome. Results. The three patients each had a complete preoperative neurologic deficit. Sagittal T1- and T2-weighted magnetic resonance images of the spine proved to have high sensitivity for defining the type of bleeding and delineating the craniocaudal extension of the hematoma. Surgical evacuation was performed within 26 hours after the onset of symptoms. Intraoperative findings showed the hematoma to be confined between the dura and the arachnoid in two patients, and to be associated with rupture into the subarachnoid space in one patient. Postoperative recovery was incomplete in two patients, and did not improve in the remaining patient. Conclusions. Spinal subdural hematoma must be considered in patients under anticoagulant therapy with spontaneous signs of acute spinal cord or cauda equina compression. Magnetic resonance imaging with sagittal T1- and T2-weighted images were adequate and reliable for diagnosis of spinal subdural hematoma. On the basis of previous studies and the authors’ intraoperative findings, spinal subdural hematomas could be viewed as spinal dural border hematomas. The level of preoperative neurologic deficit seemed to be critical for recovery despite prompt surgical evacuation.

Markers of Recurrence and Long-Term Morbidity in Craniopharyngioma: A Systematic Analysis of 171 Patients

CONTEXT Craniopharyngiomas are often associated with an unfavorable prognosis, but data on their long-term consequences are sparse. OBJECTIVE The aim of the study was to identify markers of recurrence and factors associated with compromised social rehabilitation and altered quality of life in a large cohort of patients with either childhood-onset (CO) or adult-onset craniopharyngioma. METHODS Retrospective analysis was performed for 171 patients treated for craniopharyngioma in two academic centers in France between 1972 and 2009. For each subject, data were collected concerning clinical presentation, imaging features, visual sequelae, endocrine and metabolic impact, treatment modalities (surgery, radiotherapy), recurrence-free survival rate, and social insertion, as well as answers to the WHO-QOL BREF questionnaire. RESULTS A total of 65 CO and 106 adult-onset patients were reviewed. If CO was diagnosed before the age of 10 yr, this was associated with a higher incidence of obesity, blindness, and panhypopituitarism, and only 40.7% of subjects had adequate work or school attendance compared to 72.4% of patients with later disease onset. Initial symptoms of intracranial hypertension (SIHT), pterional surgery, and multiple surgery were associated with obesity and poorer social insertion. No determinant of quality of life was identified. In the subgroup of patients treated in the 1990s and later, the progression rate was 59.4% in patients with residual tumor on magnetic resonance imaging compared with a 19.8% recurrence rate in the group with apparently complete resection. Recurrence/progression correlates significantly with male gender, early onset (before 10 yr), and SIHT, but only SIHT at presentation remained a significant predictor with multivariate analysis. CONCLUSIONS Craniopharyngioma continues to be associated with severe outcomes. Higher morbidity rates are found in patients with early-onset disease (before 10 yr), initial SIHT, or in whom pterional surgery was required. Markers of recurrence are difficult to identify, with SIHT being the most powerful predictor.

Classification of surgical processes using dynamic time warping

In the creation of new computer-assisted intervention systems, Surgical Process Models (SPMs) are an emerging concept used for analyzing and assessing surgical interventions. SPMs represent Surgical Processes (SPs) which are formalized as symbolic structured descriptions of surgical interventions using a pre-defined level of granularity and a dedicated terminology. In this context, one major challenge is the creation of new metrics for the comparison and the evaluation of SPs. Thus, correlations between these metrics and pre-operative data are used to classify surgeries and highlight specific information on the surgery itself and on the surgeon, such as his/her level of expertise. In this paper, we explore the automatic classification of a set of SPs based on the Dynamic Time Warping (DTW) algorithm. DTW is used to compute a similarity measure between two SPs that focuses on the different types of activities performed during surgery and their sequencing, by minimizing time differences. Indeed, it turns out to be a complementary approach to the classical methods that only focus on differences in the time and the number of activities. Experiments were carried out on 24 lumbar disk herniation surgeries to discriminate the surgeons level of expertise according to a prior classification of SPs. Supervised and unsupervised classification experiments have shown that this approach was able to automatically identify groups of surgeons according to their level of expertise (senior and junior), and opens many perspectives for the creation of new metrics for comparing and evaluating surgeries.

A Framework for the Recognition of High-Level Surgical Tasks From Video Images for Cataract Surgeries

The need for a better integration of the new generation of computer-assisted-surgical systems has been recently emphasized. One necessity to achieve this objective is to retrieve data from the operating room (OR) with different sensors, then to derive models from these data. Recently, the use of videos from cameras in the OR has demonstrated its efficiency. In this paper, we propose a framework to assist in the development of systems for the automatic recognition of high-level surgical tasks using microscope videos analysis. We validated its use on cataract procedures. The idea is to combine state-of-the-art computer vision techniques with time series analysis. The first step of the framework consisted in the definition of several visual cues for extracting semantic information, therefore, characterizing each frame of the video. Five different pieces of image-based classifiers were, therefore, implemented. A step of pupil segmentation was also applied for dedicated visual cue detection. Time series classification algorithms were then applied to model time-varying data. Dynamic time warping and hidden Markov models were tested. This association combined the advantages of all methods for better understanding of the problem. The framework was finally validated through various studies. Six binary visual cues were chosen along with 12 phases to detect, obtaining accuracies of 94%.

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.

Model of surgical procedures for multimodal image-guided neurosurgery.

Objective: Improvement of the planning stage of image-guided surgery requires a better anticipation of the surgical procedure and its anatomical and functional environment. This anticipation should be provided by acquisition of multimodal medical images of the patient and by a better understanding of surgical procedures. In this paper, we propose improvements to the planning and performance of multimodal image-guided neurosurgery through the use of information models related to neurosurgical procedures. Materials and Methods: A new generic model of surgical procedures is introduced in the context of multimodal image-guided craniotomies. The basic principle of the model is to break down the surgical procedure into a sequence of steps denning the surgical script. In the model, a step is defined by an action. The model assigns to each surgical step a list of image entities extracted from multimodal preoperative images (i.e., anatomical and/or functional images) which are relevant to the performance of that particular step. A semantic validation of the model was performed by instantiating the model entities for 29 surgical procedures. Results: The resulting generic model is described by a UML class diagram and a textual description. The validation showed the relevance of the model, confirming the main underlying assumptions. It also provided some leads to improve the model. Conclusion: While further validation is needed, the initial benefits of this approach can already be outlined. It should add real value to the different levels of image-guided surgery, from preprocessing to planning, as well as during surgery. Models of surgical procedures can manage image data according to the surgical script, which should lead to better anticipation of surgery through the development of simulation tools. Furthermore, the models may improve the performance of surgery using microscope-based neuronavigation systems by making it possible to adapt both visualization and interaction features of multimodal preoperative images according to the model.

Results in the operative treatment of elderly patients with spinal meningiomas.

Study Design. Thirty consecutive patients over 70 years of age who were operated on for spinal meningiomas are presented to assess surgical criteria and postoperative outcome. Objectives. To assess the outcome of surgically treated spinal meningiomas in patients in their eighth or ninth decade of life and to analyze the possible role of some prognostic factors. Summary of Background Data. The ageing of the population in the industrial nations has led to increased findings of benign spinal tumors, namely meningiomas, in the elderly. These slow-growing tumors may prevent these patients from leading an autonomous life. Little is known about the outcome of spinal meningioma surgery in patients of 70 years or older because the number of these patients, although increasing, is still small. Methods. Thirty consecutive patients over 70 years of age (mean age, 77.1 years) were operated on for spinal meningiomas between 1986 and 2001. The preoperative neurologic status of the patients was graded with the Solero score, and the general health conditions were staged according to the American Society of Anesthesiology classification. Total tumor removal was achieved in 27 patients. The follow-up period ranged from 17 to 173 months (mean, 62.7 months). Results. There was no operative mortality, and morbidity was not significant. Although not significant, neurologic outcome was better in patients with a low preoperative Solero score than those with a high one (P = 0.06). Clinical outcome was not influenced by the duration of symptoms before surgery or preoperative American Society of Anesthesiology classification. No recurrence was observed during the follow-up period. Conclusions. Neurologic outcome following surgery was favorable in the vast majority of patients, with no mortality or significant morbidity. Surgery is the only treatment in elderly patients with symptomatic spinal meningiomas, even those with a poor preoperative neurologic condition, whenever there is an acceptable risk from an anesthesiological point of view.

RECORDING OF SURGICAL PROCESSES: A STUDY COMPARING SENIOR AND JUNIOR NEUROSURGEONS DURING LUMBAR DISC HERNIATION SURGERY

BACKGROUND: Evaluating surgical practice in the operating room is difficult, and its assessment is largely subjective. OBJECTIVE: Recording of standardized spine surgery processes was conducted to ascertain whether any significant differences in surgical practice could be observed between senior and junior neurosurgeons. METHODS: Twenty-four procedures of lumbar discectomies were consecutively recorded by a senior neurosurgeon. In 12 cases, surgery was entirely performed by a senior neurosurgeon with the aid of a resident, and in the 12 remaining cases, surgery was performed by a resident with the aid of a senior neurosurgeon. The data recorded were general parameters (operating time for the whole procedure and for each step), and general and specific parameters of the surgeons activities (number of manual gestures, number and duration of actions performed, use of the instruments, and use of interventions on anatomic structures). The Mann-Whitney U test was used for comparison between the 2 groups of neurosurgeons. RESULTS: The operating time was statistically lower for the group of senior surgeons. The seniors statistically demonstrated greater economy in time and in gestures during the closure step, for sewing and for the use of scissors, needle holders, and forceps. The senior surgeons statistically worked for a shorter time on the skin and used fewer manual gestures on the thoracolumbalis fascia. The number of changes in microscope position was also statistically lower for this group. CONCLUSION: There is a relationship between surgical practice, as determined by a method of objective measurement using observation software, and surgical experience: gesture economy evolves with seniority.