Integrated-boost IMRT or 3-D-CRT using FET-PET based auto-contoured target volume delineation for glioblastoma multiforme - a dosimetric comparison

<p>Abstract</p> <p>Background</p> <p>Biological brain tumor imaging using O-(2-[¹⁸F]fluoroethyl)-L-tyrosine (FET)-PET combined with inverse treatment planning for locally restricted dose escalation in patients with glioblastoma multiforme seems to be a promising approach.</p> <p>The aim of this study was to compare inverse with forward treatment planning for an integrated boost dose application in patients suffering from a glioblastoma multiforme, while biological target volumes are based on FET-PET and MRI data sets.</p> <p>Methods</p> <p>In 16 glioblastoma patients an intensity-modulated radiotherapy technique comprising an integrated boost (IB-IMRT) and a 3-dimensional conventional radiotherapy (3D-CRT) technique were generated for dosimetric comparison. FET-PET, MRI and treatment planning CT (P-CT) were co-registrated. The integrated boost volume (PTV1) was auto-contoured using a cut-off tumor-to-brain ratio (TBR) of ≥ 1.6 from FET-PET. PTV2 delineation was MRI-based. The total dose was prescribed to 72 and 60 Gy for PTV1 and PTV2, using daily fractions of 2.4 and 2 Gy.</p> <p>Results</p> <p>After auto-contouring of PTV1 a marked target shape complexity had an impact on the dosimetric outcome. Patients with 3-4 PTV1 subvolumes vs. a single volume revealed a significant decrease in mean dose (67.7 vs. 70.6 Gy). From convex to complex shaped PTV1 mean doses decreased from 71.3 Gy to 67.7 Gy. The homogeneity and conformity for PTV1 and PTV2 was significantly improved with IB-IMRT. With the use of IB-IMRT the minimum dose within PTV1 (61.1 vs. 57.4 Gy) and PTV2 (51.4 vs. 40.9 Gy) increased significantly, and the mean EUD for PTV2 was improved (59.9 vs. 55.3 Gy, p < 0.01). The EUD for PTV1 was only slightly improved (68.3 vs. 67.3 Gy). The EUD for the brain was equal with both planning techniques.</p> <p>Conclusion</p> <p>In the presented planning study the integrated boost concept based on inversely planned IB-IMRT is feasible. The FET-PET-based automatically contoured PTV1 can lead to very complex geometric configurations, limiting the achievable mean dose in the boost volume. With IB-IMRT a better homogeneity and conformity, compared to 3D-CRT, could be achieved.</p

Hoxb1 Controls Anteroposterior Identity of Vestibular Projection Neurons

The vestibular nuclear complex (VNC) consists of a collection of sensory relay nuclei that integrates and relays information essential for coordination of eye movements, balance, and posture. Spanning the majority of the hindbrain alar plate, the rhombomere (r) origin and projection pattern of the VNC have been characterized in descriptive works using neuroanatomical tracing. However, neither the molecular identity nor developmental regulation of individual nucleus of the VNC has been determined. To begin to address this issue, we found that Hoxb1 is required for the anterior-posterior (AP) identity of precursors that contribute to the lateral vestibular nucleus (LVN). Using a gene-targeted Hoxb1-GFP reporter in the mouse, we show that the LVN precursors originate exclusively from r4 and project to the spinal cord in the stereotypic pattern of the lateral vestibulospinal tract that provides input into spinal motoneurons driving extensor muscles of the limb. The r4-derived LVN precursors express the transcription factors Phox2a and Lbx1, and the glutamatergic marker Vglut2, which together defines them as dB2 neurons. Loss of Hoxb1 function does not alter the glutamatergic phenotype of dB2 neurons, but alters their stereotyped spinal cord projection. Moreover, at the expense of Phox2a, the glutamatergic determinants Lmx1b and Tlx3 were ectopically expressed by dB2 neurons. Our study suggests that the Hox genes determine the AP identity and diversity of vestibular precursors, including their output target, by coordinating the expression of neurotransmitter determinant and target selection properties along the AP axis

Segment-Specific Neuronal Subtype Specification by the Integration of Anteroposterior and Temporal Cues

To address the question of how neuronal diversity is achieved throughout the CNS, this study provides evidence of modulation of neural progenitor cell “output” along the body axis by integration of local anteroposterior and temporal cues

Diffuse glioma growth: a guerilla war

In contrast to almost all other brain tumors, diffuse gliomas infiltrate extensively in the neuropil. This growth pattern is a major factor in therapeutic failure. Diffuse infiltrative glioma cells show some similarities with guerilla warriors. Histopathologically, the tumor cells tend to invade individually or in small groups in between the dense network of neuronal and glial cell processes. Meanwhile, in large areas of diffuse gliomas the tumor cells abuse pre-existent “supply lines” for oxygen and nutrients rather than constructing their own. Radiological visualization of the invasive front of diffuse gliomas is difficult. Although the knowledge about migration of (tumor)cells is rapidly increasing, the exact molecular mechanisms underlying infiltration of glioma cells in the neuropil have not yet been elucidated. As the efficacy of conventional methods to fight diffuse infiltrative glioma cells is limited, a more targeted (“search & destroy”) tactic may be needed for these tumors. Hopefully, the study of original human glioma tissue and of genotypically and phenotypically relevant glioma models will soon provide information about the Achilles heel of diffuse infiltrative glioma cells that can be used for more effective therapeutic strategies

Re-defining response and treatment effects for neuro-oncology immunotherapy clinical trials

In much of medical oncology, including neuro-oncology, there is great interest to evaluate the therapeutic potential of immune-based therapies including vaccines, adoptive T cell strategies and modulators of immune checkpoint regulators such as cytotoxic T lymphocyte antigen 4 and programmed death 1. Immune-based treatments exert an indirect anti-tumor effect by generating potent, tumor-targeting immune responses. Robust anti-tumor immune responses have been shown to achieve encouraging radiographic responses across the spectrum of applied immunotherapeutics which are felt to be indicative of a bona fide anti-tumor effect. Conversely, worsening of imaging findings, particularly early in the course of immunotherapy administration, can be challenging to interpret with growing evidence demonstrating that at least a subset of such patients ultimately will derive meaningful clinical benefit. The immune related response criteria were generated to provide guidance regarding the interpretation of such complex imaging findings, for general medical oncologists prescribing immunotherapeutics. An analogous effort that addresses challenges associated with imaging assessment and incorporates nuances associated with neuro-oncology patients is underway and is referred to as the immunotherapy response assessment in neuro-oncology criteria

Pseudoprogression, radionecrosis, inflammation or true tumor progression? challenges associated with glioblastoma response assessment in an evolving therapeutic landscape

The wide variety of treatment options that exist for glioblastoma, including surgery, ionizing radiation, anti-neoplastic chemotherapies, anti-angiogenic therapies, and active or passive immunotherapies, all may alter aspects of vascular permeability within the tumor and/or normal parenchyma. These alterations manifest as changes in the degree of contrast enhancement or T2-weighted signal hyperintensity on standard anatomic MRI scans, posing a potential challenge for accurate radiographic response assessment for identifying anti-tumor effects. The current review highlights the challenges that remain in differentiating true disease progression from changes due to radiation therapy, including pseudoprogression and radionecrosis, as well as immune or inflammatory changes that may occur as either an undesired result of cytotoxic therapy or as a desired consequence of immunotherapies

The recruitment of SOX/OCT complexes and the differential activity of HOXA1 and HOXB1 modulate the Hoxb1 auto-regulatory enhancer function

Regionally restricted expression patterns of Hox genes in developing embryos rely on auto-, cross-, and para-regulatory transcriptional elements. One example is the Hoxb1 auto-regulatory element (b1-ARE), which drives expression of Hoxb1 in the fourth rhombomere of the hindbrain, We previously showed that HOXB1 and PBX1 activate transcription from the b1-ARE: by binding to sequences required for the expression of a reporter gene in rhombomere 4 in vivo, We now report: that in embryonal carcinoma cells, which retain characteristics of primitive neuroectodermal cells, the b1-ARE displays higher basal and HOX/PBX-induced activities than in other cell backgrounds. We have identified a bipartite-binding site for SOX/OCT heterodimers within the b1-ARE that accounts for its cell context-specific activity and is required for maximal transcriptional activity of HOX/PBX complexes in embryonal carcinoma cells. Furthermore, we found that in an embryonal carcinoma cell background, HOXB1 has a significantly higher transcriptional activity than its paralog HOXA1. We map the determinants for this differential activity within the HOXB1 N-terminal transcriptional activation domain. By using analysis in transgenic and HOXA1 mutant mice, we extended these findings on the differential activities of HOXA1 and HOXB1 in vivo, and we demonstrated that they are important for regulating aspects of HOXB1 expression in the hindbrain. We found that mutation of the SOX/OCT site and targeted inactivation of Hoxa1 both impair the response of the b1-ARE to retinoic acid in transgenic mice. Our results show that Hoxa1 is the primary mediator of the response of b1-ARE to retinoic acid in vivo and that this function is dependent on the binding of SOX/OCT heterodimers to the b1-ARE. These results uncover novel functional differences between Hox paralogs and their modulators