The brain tissue response to surgical injury and its possible contribution to glioma recurrence.

Surgery is the first line therapy for glioma. However, glioma recurs in 90 % of the patients in the resection margin. The impact of surgical brain injury (SBI) on glioma recurrence is largely overlooked. Herein, we review some of the mechanisms involved in tissue repair that may impact glioma recurrence at the resection margin. Many processes or molecules involved in tissue repair after brain injury are also critical for glioma growth. They include a wide array of secreted growth factors, cytokines and transcription factors including NFКB and STAT3 which in turn activate proliferative and anti-apoptotic genes and processes such as angiogenesis and inflammation. Because some residual glioma cells always remain in the tumor resection margin, there are now compelling arguments to suggest that some aspects of the brain tissue response to SBI can also participate to glioma recurrence at the resection margin. Brain tissue response to SBI recruits angiogenesis and inflammation that precede and then follow tumor recurrence at the resection margin. The healing response to SBI is double edged, as inflammation is involved in regeneration and healing, and has both pro- and anti-tumorigenic functions. A promising therapeutic approach is to normalize and re-educate the molecular and cellular responses at the resection margin to promote anti-tumorigenic processes involved in healing while inhibiting pro-tumorigenic activities. Manipulation of the inflammatory response to SBI to prevent local recurrence could also enhance the efficacy of other therapies such as immunotherapy. However, our current knowledge is far from sufficient to achieve this goal. Acknowledging, understanding and manipulating the double-edged role played by SBI in glioma recurrence is surely challenging, but it cannot be longer delayed.

Translation of the ecological trap concept to glioma therapy: the cancer cell trap concept.

Viewing tumors as ecosystems offers the opportunity to consider how ecological concepts can be translated to novel therapeutic perspectives. The ecological trap concept emerged approximately half a century ago when it was observed that animals can prefer an environment of low quality for survival over other available environments of higher quality. The presence of such a trap can drive a local population to extinction. The cancer cell trap concept is the translation of the ecological trap into glioma therapy. It exploits and diverts the invasive potential of glioma cells by guiding their migration towards specific locations where a local therapy can be delivered efficiently. This illustrates how an ecological concept can change therapeutic obstacles into therapeutic tools.

The growth of the foramen magnum in Crouzon syndrome.

BACKGROUND: Though the craniovertebral junction is often abnormal in children with Crouzon's syndrome, no study had measured accurately the size of their foramen magnum (FM). PATIENTS AND METHODS: We compared the FM size (area, diameters) on computed tomography examination in 21 children with a genetically confirmed Crouzon's syndrome prior to any surgery and in 23 control children without craniofacial abnormalities. We extrapolated the growth pattern in both groups. RESULTS: We found a statistically significant smaller FM area (p=0.0228), FM sagittal diameter (p=0.0287), and FM sagittal posterior diameter (p=0.0023) in children with Crouzon's syndrome. No differences were detected with regard to the transversal diameter. Hydrocephalus in children with Crouzon's syndrome was associated with a small FM area (p=0.05), small sagittal diameter (p=0.023), small sagittal posterior diameter (p=0.0173), and reduced transversal diameter (p=0.03985). No association of the aforementioned findings was found with the position of the cerebellar tonsils or the lambdoid suture functional state (open or fused). Comparable results were observed among the two genetic forms (exon 8 or 10 mutations). Concerning the growth pattern, a first phase of rapid increase and a second phase of slow increase could be recognized in all the measurements in both populations, though with some significant differences. DISCUSSION AND CONCLUSIONS: The growth of FM follows a biphasic pattern in both Crouzon's and control children. The sagittal diameter and the global size of the FM are mostly affected in children with Crouzon's syndrome. The small FM, especially its posterior part, is likely to play a key role in the physiopathology of hydrocephalus.

Operation and Chemotherapy: Prognostic Factors for Lung Cancer With One Synchronous Metastasis.

BACKGROUND: Stage IV non-small cell lung cancer (NSCLC) is considered incurable; however, some patients with only few metastases may benefit from treatment with a curative intent. We aimed to identify the prognostic factors for stage IV NSCLC with synchronous solitary M1. METHODS: A database constructed from our weekly multidisciplinary thoracic oncology meetings was retrospectively screened from 1993 to 2012. Consecutive patients with NSCLC stages I to IV were included. RESULTS: Of the 6,760 patients found, 4,832 patients were studied. Among the 1,592 patients (33%) with stage IV NSCLC, 109 (7%) had a synchronous solitary M1. Metastasis involved the brain in 64% of patients. Median overall survival was significantly longer in synchronous solitary M1 than in other stage IV (18.9 months, interquartile range [IQR]: 9.9 to 34.6 months versus 6.1 months, IQR: 2.3 to 13.7 months], respectively, p < 10-4). Among patients with synchronous solitary M1, 90 (83%) received a local treatment with curative intent at the primary and metastatic sites. Factors independently associated with survival were age older than 63 years (hazard ratio [HR] 1.63, 95% confidence interval [CI]: 1.01 to 2.63), Performance status of 3 or 4 (HR 7.91, 95% CI: 2.23 to 28.03), use of chemotherapy (HR 0.38, 95% CI: 0.23 to 0.64), and operation conducted at both sites (HR 0.35, 95% CI: 0.19 to 0.65). CONCLUSIONS: Synchronous solitary M1 treated with chemotherapy and operation at both sites resulted in better survival. Survival of NSCLC with synchronous solitary M1 was more similar to stage III than other stage IV NSCLCs. The eighth TNM classification takes this into account by distinguishing between stages M1b and M1c.

Imaging and histological characterization of a human brain xenograft in pig: the first induced glioma model in a large animal.

The prognosis of glioblastoma remains poor despite significant improvement in cytoreductive surgery, external irradiation and new approach of systemic treatment as antiangiogenic therapy. One of the issues is the low concentration in the infiltrated parenchyma of therapeutic agent administered intravenously mainly due to the blood-brain barrier. An intracerebral injection is advocated to overpass this barrier, this kind of administration need a low flow and continuous injection. The development of sophisticated implanted devices for convection-enhanced delivery is a mandatory step to have a controlled released of a therapeutic agent in glioblastoma treatment. Before testing such a device in a clinical trial a serious preclinical studies are required, in order to test it in realistic conditions we have develop the first induced high grade glioma model in a non-rodent animal: the pig. 21 pigs have been implanted in the parietal lobe with human glioblastoma cell lineage under a chemical immunosuppression by ciclosporine. A MRI follow up was then realized. 15 pigs have been implanted with U87MG, 14 have presented a macroscopic significant tumor, with radiological and anatomapathological characteristics of high grade glioma. 6 pigs were implanted with G6, stem-like cells tumors of glioblastoma, 1 pig develops a macroscopic tumor. This is the first reproducible glioma model in a large animal described, it open the way to preclinical studies to test implanted devices in anatomic realistic conditions, without the ethical issues of a primate use.

A micro-silicon chip for in vivo cerebral imprint in monkey.

Access to cerebral tissue is essential to better understand the molecular mechanisms associated with neurodegenerative diseases. In this study, we present, for the first time, a new tool designed to obtain molecular and cellular cerebral imprints in the striatum of anesthetized monkeys. The imprint is obtained during a spatially controlled interaction of a chemically modified micro-silicon chip with the brain tissue. Scanning electron and immunofluorescence microscopies showed homogeneous capture of cerebral tissue. Nano-liquid chromatography-tandem mass spectrometry (nano-LC-MS/MS) analysis of proteins harvested on the chip allowed the identification of 1158 different species of proteins. The gene expression profiles of mRNA extracted from the imprint tool showed great similarity to those obtained via the gold standard approach, which is based on post-mortem sections of the same nucleus. Functional analysis of the harvested molecules confirmed the spatially controlled capture of striatal proteins implicated in dopaminergic regulation. Finally, the behavioral monitoring and histological results establish the safety of obtaining repeated cerebral imprints in striatal regions. These results demonstrate the ability of our imprint tool to explore the molecular content of deep brain regions in vivo. They open the way to the molecular exploration of brain in animal models of neurological diseases and will provide complementary information to current data mainly restricted to post-mortem samples.

Biodiversity as a barrier to glioma cell invasion.

Gliomas are extremely aggressive and lethal forms of brain cancer. Unlike many other cancer types, glioma cells rarely metastasize. They spread throughout the brain and invasiveness of glioma cells is a major cause of therapeutic failure. In plant ecosystem, biodiversity acts locally as a barrier to ecological invasion. By analogy, we hypothesize that the low cell diversity of differentiated tissues, a counterpart of their functional specificity, opens the way to local cancer cell invasion. Seeding the brain tumor microenvironment with heterogeneous cell populations could be a mean to limit cancer cell invasion by enhancing cell biodiversity.

Femoral nerve palsy following mini-open extraperitoneal lumbar approach: report of three cases and cadaveric mechanical study.

Anterior extraperitoneal exposures to the lumbar spine are being increasingly used owing to the expanding use of novel technologies to treat degenerative disc disease. Lumbar plexus injuries are potential, albeit uncommon, complications of such exposures and can lead to significant perioperative morbidity. In this report, we present three patients with thoracolumbar fractures who sustained isolated femoral nerve palsies after a mini-open extraperitoneal approach to the midlumbar spine was undertaken to perform a partial corpectomy. To further understand the pathophysiology of this nerve injury, we conducted a cadaveric experiment to evaluate the effect of performing this approach and the effect of hip positioning on linear displacement of the femoral nerve. The displacement of the femoral nerve during the anterolateral extraperitoneal exposure through a 4- to 6-cm incision was equal to 6.6% of the full femoral nerve length. Relaxation of the femoral nerve was equal to 25% of the full nerve length when the hip was flexed to 90 degrees in neutral abduction-adduction. We conclude that the anterolateral extraperitoneal exposure of the midlumbar spine can potentially stretch the femoral nerve beyond its physiologic limits, particularly in trauma cases where exposure of the lateral vertebral body necessitates substantial retraction of the psoas muscle. The avoidance of self-retaining retractors for prolonged periods of time and the positioning of the hip in flexion may help to avoid such nerve injuries.