**10. References**

[1] Schlosser, H. G., Suess, O., Vajkoczy, P., van Landeghem, F. K., Zeitz, M. & Bojarski, C. (2009 (Epub)). Confocal neurolasermicroscopy in human brain - perspectives for neurosurgery on a cellular level (including additional comments to this article). *Cen Eur Neurosurg,* 71, 1, 13-19

The next step in evaluating NLM for a diagnostic approach in humans during ongoing neurosurgery would be to utilize an adapted miniaturized confocal instrument specially designed for neurosurgery applications. The technical settings for the laser system can be directly transferred from the system used in this study. However, one important problem should be addressed concerning the reprocessing of the microscopic device. The way of reprocessing will be an essential step to use the microscope in a sterile condition within routine neurosurgical procedures. The first data in humans during ongoing neurosurgery are meanwhile available (Sanai et al., 2011 (Epub), Schlosser, H.G., Bojarski, C. (2011 (Epub)). Neurosurgery, however the problem of reprocessing is not completely fixed. The confocal laser technique for the reusable equipment has been licensed by Zeiss, Germany, for neurosurgery from its initial developer in Australia. Here the integration of NLM into a conventional microscope system is advanced including the option of navigation and matching image-guidance data. A hand-held device has been designed and used in animal research (Sankar et al., 2010) and in humans (Schlosser, H.G., Bojarski, C. 2011 (Epub)). For the reusable system used in endoscopy in the last years a setrilizablility has not been achieved. So the application in routine neurosurgical procedures is severely limited. One has to think to introduce a disposable system which is already in clinical use for different applications. An adaptation of a reusable system could be the step to provide a confocal

Furthermore, the use of contrast agents has to be adapted to the in vivo situation. We would prefer using intravenously injected fluorescein (Makale, 2007) instead of topically applied acriflavine. Fluorescein is used for decades in ophthalmology and is permitted as a medical investigational drug with a very low rate of side effects (Lipson and Yannuzzi, 1989). Moreover, fluorescein is an established contrast agent in confocal endomicroscopy in gastroenterology where it distributes the entire gastrointestinal tissue up to 250 µm in depth (Hoffman et al., 2006). When fluorescein is applied in neurosurgery one has to consider the effect of passing the blood brain barrier (BBB), presumably only a small amount of serum albumin unbound fraction of fluorescein will pass BBB and the dye mainly stay intravascular. The amount of cellular staining has to be explored in further studies. In the neoplastic tissue the vessels probably will show a different pattern compared to healthy brain. We would expect abnormal branching and looping of the vasculature as well as abrupt changes in diameter contributing to stricture-like structures. The extravascular distribution of fluorescein, however, in a disturbed BBB as in neoplastic conditions may

The next step after defining the pathologies in an NLM atlas and after ascertain the affiliated operative proceeding clinical studies have to proof the benefit for the patients depending on

[1] Schlosser, H. G., Suess, O., Vajkoczy, P., van Landeghem, F. K., Zeitz, M. & Bojarski, C.

(2009 (Epub)). Confocal neurolasermicroscopy in human brain - perspectives for neurosurgery on a cellular level (including additional comments to this article). *Cen* 

neurolasermicroscope for routine clinical use in neurosurgery.

show the pathologic vascularisation in combination with a cellular staining.

**9. Further developments** 

the disease.

**10. References** 

*Eur Neurosurg,* 71, 1, 13-19


**20** 

Patrick Beauchesne *Neuro-Oncology Department,* 

*CHU de NANCY* 

*France* 

**Ultrafractionated Radiation Therapy** 

**A New and Promising Radiotherapy Schedule for Glioblastoma Patients** 

Malignant glioma is one of the most radio-resistant tumor types and accounts for approximately 60% of all primary brain tumors in adults (Behin et al., 2003; Black, 1991a, 1991b; DeAngelis, 2001). There are three distinct histological types: anaplastic astrocytoma (AA), anaplastic oligodendroglioma (AO), and glioblastoma multiforme (GBM). The prognosis of malignant glioma patients remains dismal (Behin et al., 2003; Black, 1991a, 1991b; De Angelis, 2001). The median survival for patients with newly diagnosed GBM is 8 to 15 months, prognosis is slightly better for newly diagnosed AA with a median survival of 24 to 36 months, and the prognosis for AO gives a median survival of 60 months (Behin et al., 2003; Black, 1991a, 1991b; De Angelis, 2001). For AA and GBM, the standard of care consists of surgical resection of as much of the tumor as is considered to be safe, followed by radiation and chemotherapy and has been so for many decades (Behin et al., 2003; Black, 1991a, 1991b; DeAngelis, 2001, Fine et al., 1993; Stewart, 2002; Walker et al., 1978, 1980). A new standard procedure for GBM has recently been defined by the EORTC phase III trial which randomized patients in two groups, receiving either temozolomide (TMZ) concomitant and adjuvant to radiation therapy or radiation therapy alone (Stupp et al., 2005). A significant increase in overall survival (OS) was seen in the radiation therapy plus TMZ group compared to the radiation therapy alone group. Survival rates were respectively 14.6 and 12.1 months. For AO, the standard treatment is surgical resection followed by radiation therapy (Stupp et al., 2005). Adjuvant chemotherapy does not provide significant

Radiation therapy remains the backbone of care for glioblastomas, even in patients who have undergone a prior presumed complete resection. The infiltrative nature of these tumors makes a truly complete resection nearly impossible in most cases (Behin et al., 2003; Black, 1991a, 1991b; DeAngelis, 2001, Fine et al., 1993; Hall, 1978; Stewart, 2002; Walker et al., 1978, 1980). Standard fractionated radiation therapy delivers a total radiation dose of 60 Gy given in 30 fractions over 6 weeks. The target is usually the tumor bulk as visualized on CT or MRI, with a wide margin of 2-3 cm (Behin et al., 2003; Black, 1991a, 1991b; DeAngelis,

**1. Introduction** 

benefits in OS (Van den Bent et al., 2006).

**(3 Daily Doses of 0.75 Gy) -** 

