Whole-brain irradiation with hippocampal sparing and dose escalation on metastases: neurocognitive testing and biological imaging (HIPPORAD) - a phase II prospective randomized multicenter trial (NOA-14, ARO 2015-3, DKTK-ROG).

Background: Whole brain radiation therapy (WBRT) is the standard therapy for multiple brain metastases. However, WBRT has a poor local tumor control and is associated with a decline in neurocognitive function (NCF). Aim of this trial is to assess the efficacy and safety of a new treatment method, the WBRT with hippocampus avoidance (HA) combined with the simultaneous integrated boost (SIB) on metastases/resection cavities (HA-WBRT+SIB).

Diffusion-weighted MRI and ADC versus FET-PET and GdT1w-MRI for gross tumor volume (GTV) delineation in re-irradiation of recurrent glioblastoma.

Background And Purpose: GTV definition for re-irradiation treatment planning in recurrent glioblastoma (rGBM) is usually based on contrast-enhanced MRI (GdT1w-MRI) and, for an increased specificity, on amino acid PET. Diffusion-weighted (DWI) MRI and ADC maps can reveal regions of high cellularity as surrogate for active tumor. The objective of this study was to compare the localization and quality of diffusion restriction foci (GTV-ADClow) with FET-PET (GTV-PET) and GdT1w-MRI (GTV-GdT1w-MRI).

Local control and possibility of tailored salvage after hypofractionated stereotactic radiotherapy of the cavity after brain metastases resection.

In patients undergoing surgical resection of brain metastases, the risk of local recurrence remains high. Adjuvant whole brain radiation therapy (WBRT) can reduce the risk of local relapse but fails to improve overall survival. At two tertiary care centers in Germany, a retrospective study was performed to evaluate the role of hypofractionated stereotactic radiotherapy (HFSRT) in patients with brain metastases after surgical resection.

Multicenter analysis of stereotactic radiotherapy of the resection cavity in patients with brain metastases.

Brain metastases show a recurrence rate of about 50% after surgical resection. Adjuvant radiotherapy can prevent progression; however, whole-brain radiotherapy (WBRT) can be associated with significant side effects. Local hypofractionated stereotactic radiotherapy (HFSRT) is a good alternative to provide local control with minimal toxicity.

Clinical outcome after high-precision radiotherapy for skull base meningiomas: Pooled data from three large German centers for radiation oncology.

Purpose: To evaluate outcome in patients with base of skull meningiomas treated with modern high precision radiation therapy (RT) techniques.

Patients And Methods: 927 patients from three centers were treated with either radiosurgery or fractionated high-precision RT for meningiomas. Treatment planning was based on CT and MRI following institutional guidelines.

Local control and overall survival after frameless radiosurgery: A single center experience.

Introduction: Stereotactic radiosurgery (SRS) has been increasingly advocated for 1-3 small brain metastases. The goal of this study was to evaluate the clinical results in patients with brain metastases treated with LINAC-based SRS using a thermoplastic mask (non-invasive fixation system) and Image-Guided Radiotherapy (IGRT).

Material And Methods: In this single-institution study 48 patients with 77 brain metastases were treated between February 2012 and January 2014.

Re-irradiation of recurrent gliomas: pooled analysis and validation of an established prognostic score-report of the Radiation Oncology Group (ROG) of the German Cancer Consortium (DKTK).

The heterogeneity of high-grade glioma recurrences remains an ongoing challenge for the interdisciplinary neurooncology team. Response to re-irradiation (re-RT) is heterogeneous, and survival data depend on prognostic factors such as tumor volume, primary histology, age, the possibility of reresection, or time between primary diagnosis and initial RT and re-RT. In the present pooled analysis, we gathered data from radiooncology centers of the DKTK Consortium and used it to validate the established prognostic score by Combs et al.

Biological imaging for individualized therapy in radiation oncology: part II medical and clinical aspects.

Positron emission tomography and multiparametric MRI provide crucial information concerning tumor extent and normal tissue anatomy. Moreover, they are able to visualize biological characteristics of the tumor, which can be considered in the radiation treatment planning and monitoring. In this review we discuss the impact of biological imaging positron emission tomography and multiparametric MRI for radiation oncology, based on the data of the literature and on the experience of our own institution in this field.

Independent validation of a new reirradiation risk score (RRRS) for glioma patients predicting post-recurrence survival: A multicenter DKTK/ROG analysis.

Background And Purpose: Reirradiation (reRT) is a valid option with considerable efficacy in patients with recurrent high-grade glioma, but it is still not known which patients might be optimal candidates for a second course of irradiation. This study validated a newly developed prognostic score independently in an external patient cohort.

Material And Methods: The reRT risk score (RRRS) is based on a linear combination of initial histology, clinical performance status, and age derived from a multivariable model of 353 patients.

Validation of the Graded Prognostic Assessment for Melanoma Using Molecular Markers (Melanoma-molGPA).

Background: It has been suggested to replace the diagnosis-specific graded prognostic assessment (DS-GPA, based on performance status and number of brain metastases) for patients with primary malignant melanoma with the new Melanoma-molGPA. The latter is a more complex assessment, which also includes BRAF mutation status, age and extracranial metastases. To test the performance of the Melanoma-molGPA, we performed a validation study of this new survival prediction tool.

Validation of the graded prognostic assessment for lung cancer with brain metastases using molecular markers (lung-molGPA).

Background: Many patients with brain metastases from non-small cell lung cancer have limited survival, while others survive for several years, depending on patterns of spread, EGFR and ALK alterations, among others. The purpose of this study was to validate a new prognostic model (Lung-molGPA) originally derived from a North American database.

Patients And Methods: This retrospective study included 269 German and Norwegian patients treated with individualized approaches, always including brain radiotherapy.

The TNM 8 M1b and M1c classification for non-small cell lung cancer in a cohort of patients with brain metastases.

Background And Purpose: According to the recent TNM 8 classification, patients with metastatic non-small cell lung cancer (NSCLC) and single extrathoracic metastasis should be classified as stage M1b, while those with 2 or more metastases comprise stage M1c. The purpose of this study was to analyze the impact of this classification in patients with brain metastases.

Materials And Methods: This retrospective study included 172 patients treated with individualized approaches.

Amino-acid PET versus MRI guided re-irradiation in patients with recurrent glioblastoma multiforme (GLIAA) - protocol of a randomized phase II trial (NOA 10/ARO 2013-1).

Background: The higher specificity of amino-acid positron emission tomography (AA-PET) in the diagnosis of gliomas, as well as in the differentiation between recurrence and treatment-related alterations, in comparison to contrast enhancement in T1-weighted MRI was demonstrated in many studies and is the rationale for their implementation into radiation oncology treatment planning. Several clinical trials have demonstrated the significant differences between AA-PET and standard MRI concerning the definition of the gross tumor volume (GTV). A small single-center non-randomized prospective study in patients with recurrent high grade gliomas treated with stereotactic fractionated radiotherapy (SFRT) showed a significant improvement in survival when AA-PET was integrated in target volume delineation, in comparison to patients treated based on CT/MRI alone.

Visualization of Deformable Image Registration Quality Using Local Image Dissimilarity.

Deformable image registration (DIR) has the potential to improve modern radiotherapy in many aspects, including volume definition, treatment planning and image-guided adaptive radiotherapy. Studies have shown its possible clinical benefits. However, measuring DIR accuracy is difficult without known ground truth, but necessary before integration in the radiotherapy workflow.

Interactive contour delineation of organs at risk in radiotherapy: Clinical evaluation on NSCLC patients.

Purpose: Accurate delineation of organs at risk (OARs) on computed tomography (CT) image is required for radiation treatment planning (RTP). Manual delineation of OARs being time consuming and prone to high interobserver variability, many (semi-) automatic methods have been proposed. However, most of them are specific to a particular OAR.

Stereotactic fractionated radiotherapy of the resection cavity in patients with one to three brain metastases.

Objectives: The goal of this study is to evaluate the role of stereotactic fractionated radiotherapy (SFRT) in patients with one to three brain metastases after surgical resection.

Methods And Materials: We performed a retrospective single-institutional study in patients undergoing SFRT of surgical cavity after resection of ≤3 brain metastases. 60 patients with newly diagnosed brain metastases treated with SFRT following resection were included.

The challenge of durable brain control in patients with brain-only metastases from breast cancer.

The vast majority of patients with brain metastases from breast cancer have extracranial metastases, e.g., in the liver, lungs or bones, with serious impact on prognosis.

Whole brain irradiation with hippocampal sparing and dose escalation on multiple brain metastases: Local tumour control and survival.

Purpose: Hippocampal-avoidance whole brain radiotherapy (HA-WBRT) for multiple brain metastases may prevent treatment-related cognitive decline, compared to standard WBRT. Additionally, simultaneous integrated boost (SIB) on individual metastases may further improve the outcome. Here, we present initial data concerning local tumour control (LTC), intracranial progression-free survival (PFS), overall survival (OS), toxicity and safety for this new irradiation technique.

Variants of the electrogenic sodium bicarbonate cotransporter 1 (NBCe1) in mouse hippocampal neurons are regulated by extracellular pH changes: evidence for a Rab8a-dependent mechanism.

Changes in extracellular pH are common events in both pathological conditions and during normal brain function. In organs other than the brain, cells may respond to pH changes by trafficking of acid-base transporters. However, regulation of neuronal acid-base transporters during pH shifts is not understood.

Acidosis-induced V-ATPase trafficking in salivary ducts is initiated by cAMP/PKA/CREB pathway via regulation of Rab11b expression.

Changes in systemic acid-base homeostasis cause a series of organ-specific cellular responses, among them changes of acid-base transporter activities, and recruitment or retrieval of these transporters from intracellular pools to the plasma membrane and vice versa. The purpose of this study was to investigate the impact of protein phosphorylation in the acidosis-induced translocation of vacuolar-type H(+)-ATPase (V-ATPase) in salivary ducts and to identify molecular targets. Therefore, the human submandibular gland cell line HSG was exposed to acidosis and V-ATPase trafficking was investigated in the presence or absence of inhibitors and activators of sAC/PKA and Src/ERK signaling pathways.

Sim1 is a novel regulator in the differentiation of mouse dorsal raphe serotonergic neurons.

Background: Mesencephalic dopaminergic neurons (mDA) and serotonergic (5-HT) neurons are clinically important ventral neuronal populations. Degeneration of mDA is associated with Parkinson's disease; defects in the serotonergic system are related to depression, obsessive-compulsive disorder, and schizophrenia. Although these neuronal subpopulations reveal positional and developmental relationships, the developmental cascades that govern specification and differentiation of mDA or 5-HT neurons reveal missing determinants and are not yet understood.

Rab11b and its effector Rip11 regulate the acidosis-induced traffic of V-ATPase in salivary ducts.

Redistribution of acid-base transporters is a crucial regulatory mechanism for many types of cells to cope with extracellular pH changes. In epithelial cells, however, translocation of acid-base transporters ultimately leads to changes in vectorial transport of H+ and HCO3-. We have previously shown that the bicarbonate-secreting epithelium of salivary ducts responds to changes of systemic acid-base balance by adaptive redistribution of H+ and HCO3- transporters, thereby influencing the ionic composition and buffering capacity of saliva.

Transforming growth factor beta cooperates with persephin for dopaminergic phenotype induction.

The aim of the present study was to investigate the putative cooperative effects of transforming growth factor beta (TGF-beta) and glial cell line-derived neurotrophic factor (GDNF) family ligands in the differentiation of midbrain progenitors toward a dopaminergic phenotype. Therefore, a mouse midbrain embryonic day (E) 12 neurospheres culture was used as an experimental model. We show that neurturin and persephin (PSPN), but not GDNF, are capable of transient induction of dopaminergic neurons in vitro.

Adaptive redistribution of NBCe1-A and NBCe1-B in rat kidney proximal tubule and striated ducts of salivary glands during acid-base disturbances.

The cellular distribution of the NH2-terminal electrogenic Na+-HCO3(-) cotransporter (NBCe1) variants NBCe1-A and NBCe1-B has been investigated in rat kidney and submandibular gland (SMG) under physiological conditions and after systemic acid-base perturbations. Moreover, the in vivo data were complemented in vitro by using an immortalized cell line derived from the S1 segment of the proximal tubule (PT) of normotensive Wistar-Kyoto rats (WKPT-0293 Cl.2).

Transforming growth factor beta is required for differentiation of mouse mesencephalic progenitors into dopaminergic neurons in vitro and in vivo: ectopic induction in dorsal mesencephalon.

Tissue engineering is a prerequisite for cell replacement as therapeutic strategy for degenerative diseases, such as Parkinson's disease. In the present study, we investigated regional identity of mesencephalic neural progenitors and characterized their development toward ventral mesencephalic dopaminergic neurons. We show that neural progenitors from ventral and dorsal mouse embryonic day 12 mesencephalon exhibit regional identity in vitro.