Imaging issues specific to hadrontherapy (proton, carbon, helium therapy and other charged particles) for radiotherapy planning, setup, dose monitoring and tissue response assessment.

Imaging is critical to each step of precision radiation therapy, i.e. planning, setup, delivery and assessment of response. Hadrontherapy can be considered to deliver more precise dose distribution that may better spare normal tissues from intermediate low doses of radiation. In addition, hadrontherapy using high linear energy transfer ions may also be used for dose escalation on biological target volumes defined by functional imaging. However, the physical characteristics of hadrontherapy also make it more demanding in terms of imaging accuracy and image-based dose calculation. Some of the developments needed in imaging are specific to hadrontherapy. The current review addresses current status of imaging in proton therapy and the drawbacks of photon-based imaging for hadrons. It also addresses requirements in hadrontherapy planning with respect to multimodal imaging for proper target and organ at risk definition as well as to target putative radioresistant areas such as hypoxic ones, and with respect to dose calculation using dual energy CT, MR-proton therapy, proton radiography. Imaging modalities, such as those used in photon-based radiotherapy (intensity modulated and stereotactic radiotherapy), are somewhat already implemented or should be reaching "routine" hadrontherapy (at least proton therapy) practice in planning, repositioning and response evaluation optimizable within the next five years. Online monitoring imaging by PET, as currently developed for hadrontherapy, is already available. Its spatiotemporal limits restrict its use but similar to prompt gamma detection, represents an area of active research for the next 5 to 10 years. Because of the more demanding and specific dose deposit characteristics, developments image-guided hadrontherapy, such as specific proton imaging using tomography or ionoacoustics, as well as delivery with MR-proton therapy, may take another 10 years to reach the clinics in specific applications. Other aspects are briefly described such as range monitoring. Finally, the potential of imaging normal tissue changes and challenges to assess tumour response are discussed.

[(18)F]-fluoro-L-thymidine PET and advanced MRI for preoperative grading of gliomas.

PURPOSE: Conventional MRI based on contrast enhancement is often not sufficient in differentiating grade II from grade III and grade III from grade IV diffuse gliomas. We assessed advanced MRI, MR spectroscopy and [(18)F]-fluoro-l-thymidine ([(18)F]-FLT) PET as tools to overcome these limitations. METHODS: In this prospective study, thirty-nine patients with diffuse gliomas of grades II, III or IV underwent conventional MRI, perfusion, diffusion, proton MR spectroscopy ((1)H-MRS) and [(18)F]-FLT-PET imaging before surgery. Relative cerebral blood volume (rCBV), apparent diffusion coefficient (ADC), Cho/Cr, NAA/Cr, Cho/NAA and FLT-SUV were compared between grades. RESULTS: Cho/Cr showed significant differences between grade II and grade III gliomas (p = 0.03). To discriminate grade II from grade IV and grade III from grade IV gliomas, the most relevant parameter was the maximum value of [(18)F]-FLT uptake FLTmax (respectively, p < 0.001 and p < 0.0001). The parameter showing the best correlation with the grade was the mean value of [(18)F]-FLT uptake FLTmean (R(2) = 0.36, p < 0.0001) and FLTmax (R(2) = 0.5, p < 0.0001). CONCLUSION: Whereas advanced MRI parameters give indications for the grading of gliomas, the addition of [(18)F]-FLT-PET could be of interest for the accurate preoperative classification of diffuse gliomas, particularly for identification of doubtful grade III and IV gliomas.

Five-Year Longitudinal MRI Follow-up and (1)H Single Voxel MRS in 14 patients with Gliomatosis Treated with Temodal, Radiotherapy and Antiangiogenic Therapy.

Gliomatosis cerebri (GC) is a challenging tumor, considered to have a poor prognosis and poor response to treatments. The purpose of this study is to better understand glial tumor metabolism and post chemotherapy, radiotherapy and antiangiogenic variations in a longitudinal study to determine cerebral variation in MRS area, amplitude, and ratios of metabolites and spectral profiles during a five year longitudinal follow-up in 14 patients with gliomatosis without initial hyperperfusion and treated with chemotherapy (Temozolomide (Temodal(®))), radiotherapy and subsequent antiangiogenic therapy. The study also aimed to detect changes in infiltration, proliferation, lipids or glycolytic metabolism, as these changes could be monitored longitudinally in humans with glial brain tumors (low and high grade) after therapy, using conventional magnetic resonance imaging (MRI), spectroscopy (MRS) and MR perfusion. Most patients had first initial clinical and MRS improvement and stable MRI. After 12 to 24 chemotherapy treatment cycles MRS usually showed an increase in the Cho/Cr ratio (proliferation) and sometimes contrast enhancements. Later, the patients showed clinical deterioration and radiotherapy was started. There was an improvement with radiotherapy that lasted nine to 18 months. This was followed by a worsening that led to try antiangiogenic therapy. Later in the evolution for three patients with hyperperfusion this symptom disappeared, but proliferation, infiltration and glycolytic metabolism remained at a high level. Spectroscopic and metabolic changes often occur well before clinical deterioration and sometimes before improvement. Therefore, MRS could be more sensitive and could detect changes earlier than MRI and is sometimes predictive. Despite the difficulty, the variability and unknown factors, these repeated measurements give us a better insight into the nature of the different processes, tumor progression and could lead to better understanding of therapeutic response.

Angiopoietin-1-induced PI3-kinase activation prevents neuronal apoptosis.

Although angiopoietin-1 (Ang-1) is recognized as an endothelial growth factor, its presence in brain following an ischemic event suggests a role in the evolution of neuronal damage. Using primary neuronal cultures, we showed that neurons express Ang-1 and possess the functional angiopoietin-receptor Tie-2, which is phosphorylated in the presence of Ang-1. We further investigated in vitro whether Ang-1 could protect neurons against either excitotoxic necrosis or apoptosis induced by serum deprivation (SD). A neuroprotective effect for Ang-1 was detected exclusively in the apoptotic paradigm. Treatment of cells with the phosphatidyl-inositol 3-kinase (PI3-K) inhibitor, LY294002, inhibited Ang-1-induced phosphorylation of Akt, restored the cleavage of the effector caspase-3, and reduced the protective effect of Ang-1 against SD-induced toxicity. These findings suggest that Ang-1 has a neuroprotective effect against apoptotic stress and that this effect is dependent on the PI3-K/Akt pathway and inhibition of caspase-3 cleavage. This study provides evidence that Ang-1 is not just angiogenic but also neuroprotective. The understanding of neuroprotective mechanisms induced by Ang-1 may promote strategies based on the pleiotropic effects of angiogenic factors. Such approaches could be useful for the treatment of brain diseases in which both neuronal death and angiogenesis are involved.