The TRAMs present a novel model-independent approach providing efficient separation between tumor/nontumor tissues by adding a short MRI scan >1 h post contrast injection. The methodology uses robust acquisition sequences, providing high resolution and easy to interpret maps with minimal sensitivity to susceptibility artifacts. The presented results provide histological validation of the TRAMs and demonstrate their potential contribution to the management of brain tumor patients.

To determine the effectiveness of stereotactic radiosurgery (SRS) treatment to central nervous system (CNS) hemangioblastomas in von Hippel-Lindau disease (VHL), we analyzed long-term results in VHL patients treated with SRS. Patients were enrolled in a prospective VHL natural history study, undergoing SRS treatment of CNS hemangioblastomas. Treatment regimens, serial clinical evaluations, and longitudinal imaging data were analyzed. Twenty VHL patients (10 males and 10 females) underwent SRS treatment of 44 CNS hemangioblastomas (39 cerebellar and 5 brainstem). Mean (+/-SD) age at treatment was 37.5 +/- 12.0 years (range: 13-67). Mean follow-up was 8.5 +/- 3.2 years (range: 3.0-17.6 years). All patients were alive at last follow-up. Mean treated tumor volume was 0.5 +/- 0.7 cm(3) (range: 0.01-3.6 cm(3)). Mean prescription dose was 18.9 Gy (range: 12-24 Gy) at the tumor margin. Local control rate at 2, 5, 10, and 15 years after SRS treatment was 91%, 83%, 61%, and 51%, respectively. Univariate analysis did not identify variables associated (P > .05) with worse tumor control at last follow-up. Thirty-three percent of SRS-treated small (<1.0 cm diameter), asymptomatic tumors progressed over a long-term follow-up. There were no long-term adverse radiation effects. Although SRS treatment of hemangioblastomas in VHL has a low risk for adverse radiation effects, it is associated with diminishing control over a long-term follow-up. These results indicate that SRS should not be used to prophylactically treat asymptomatic tumors and should be reserved for the treatment of tumors that are not surgically resectable.

An external respiratory surrogate that not only highly correlates with but also quantitatively predicts internal tidal volume should be useful in guiding four-dimensional computed tomography (4DCT), as well as 4D radiation therapy (4DRT). A volumetric surrogate should have advantages over external fiducial point(s) for monitoring respiration-induced motion of the torso, which deforms in synchronization with a patient-specific breathing pattern. This study establishes a linear relationship between the external torso volume change (TVC) and lung air volume change (AVC) by validating a proposed volume conservation hypothesis (TVC = AVC) throughout the respiratory cycle using 4DCT and spirometry. Fourteen patients' torso 4DCT images and corresponding spirometric tidal volumes were acquired to examine this hypothesis. The 4DCT images were acquired using dual surrogates in ciné mode and amplitude-based binning in 12 respiratory stages, minimizing residual motion artifacts. Torso and lung volumes were calculated using threshold-based segmentation algorithms and volume changes were calculated relative to the full-exhalation stage. The TVC and AVC, as functions of respiratory stages, were compared, showing a high correlation (r = 0.992 +/- 0.005, p < 0.0001) as well as a linear relationship (slope = 1.027 +/- 0.061, R(2) = 0.980) without phase shift. The AVC was also compared to the spirometric tidal volumes, showing a similar linearity (slope = 1.030 +/- 0.092, R(2) = 0.947). In contrast, the thoracic and abdominal heights measured from 4DCT showed relatively low correlation (0.28 +/- 0.44 and 0.82 +/- 0.30, respectively) and location-dependent phase shifts. This novel approach establishes the foundation for developing an external volumetric respiratory surrogate.

An analytical approach to predict respiratory diaphragm motion should have advantages over a correlation-based method, which cannot adapt to breathing pattern changes without re-calibration for a changing correlation and/or linear coefficient. To quantitatively calculate the diaphragm motion, a new expandable 'piston' respiratory (EPR) model was proposed and tested using 4DCT torso images of 14 patients. The EPR model allows two orthogonal lung motions (with a few volumetric constraints): (1) the lungs expand (DeltaV(EXP)) with the same anterior height variation as the thoracic surface, and (2) the lungs extend (DeltaV(EXT)) with the same inferior distance as the volumetrically equivalent 'piston' diaphragm. A volume conservation rule (VCR) established previously (Li et al 2009 Phys. Med. Biol. 54 1963-78) was applied to link the external torso volume change (TVC) to internal lung volume change (LVC) via lung air volume change (AVC). As the diaphragm moves inferiorly, the vacant space above the diaphragm inside the rib cage should be filled by lung tissue with a volume equal to DeltaV(EXT) (=LVC-DeltaV(EXP)), while the volume of non-lung tissues in the thoracic cavity should conserve. It was found that DeltaV(EXP) accounted for 3-24% of the LVC in these patients. The volumetric shape of the rib cage, characterized by the variation of cavity volume per slice over the piston motion range, deviated from a hollow cylinder by -1.1% to 6.0%, and correction was made iteratively if the variation is >3%. The predictions based on the LVC and TVC (with a conversion factor) were compared with measured diaphragm displacements (averaged from six pivot points), showing excellent agreements (0.2 +/- 0.7 mm and 0.2 +/- 1.2 mm, respectively), which are within clinically acceptable tolerance. Assuming motion synchronization between the piston and points of interest along the diaphragm, point motion was estimated but at higher uncertainty ( approximately 10% +/- 4%). This analytical approach provides a patient-independent technique to calculate the patient-specific diaphragm motion, using the anatomical and respiratory volumetric constraints.

Background Ofranergene obadenovec (VB-111) is an anticancer viral therapy that demonstrated in a phase II study a survival benefit for patients with recurrent glioblastoma (rGBM) who were primed with VB-111 monotherapy that was continued after progression with concomitant bevacizumab. Methods This pivotal phase III randomized, controlled trial compared the efficacy and safety of upfront combination of VB-111 and bevacizumab versus bevacizumab monotherapy. Patients were randomized 1:1 to receive VB-111 1013 viral particles every 8 weeks in combination with bevacizumab 10 mg/kg every 2 weeks (combination arm) or bevacizumab monotherapy (control arm). The primary endpoint was overall survival (OS), and secondary endpoints were objective response rate (ORR) by Response Assessment in Neuro-Oncology (RANO) criteria and progression-free survival (PFS). Results Enrolled were 256 patients at 57 sites. Median exposure to VB-111 was 4 months. The study did not meet its primary or secondary goals. Median OS was 6.8 versus 7.9 months in the combination versus control arm (hazard ratio, 1.20; 95% CI: 0.91–1.59; P = 0.19) and ORR was 27.3% versus 21.9% (P = 0.26). A higher rate of grades 3–5 adverse events was reported in the combination arm (67% vs 40%), mainly attributed to a higher rate of CNS and flu-like/fever events. Trends for improved survival with combination treatment were seen in the subgroup of patients with smaller tumors and in patients who had a posttreatment febrile reaction. Conclusions In this study, upfront concomitant administration of VB-111 and bevacizumab failed to improve outcomes in rGBM. Change of treatment regimen, with the lack of VB-111 monotherapy priming, may explain the differences from the favorable phase II results. Clinical trials registration NCT02511405

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The current standard of care for newly diagnosed glioblastoma multiforme (GBM) is resection followed by radiotherapy with concomitant and adjuvant temozolomide. Recent studies suggest that nearly half of the patients with early radiological deterioration post treatment do not suffer from tumor recurrence but from pseudoprogression. Similarly, a significant number of patients with brain metastases suffer from radiation necrosis following radiation treatments. Conventional MRI is currently unable to differentiate tumor progression from treatment-induced effects. The ability to clearly differentiate tumor from non-tumoral tissues is crucial for appropriate patient management. Ten patients with primary brain tumors and 10 patients with brain metastases were scanned by delayed contrast extravasation MRI prior to surgery. Enhancement subtraction maps calculated from high resolution MR images acquired up to 75 min after contrast administration were used for obtaining stereotactic biopsies. Histological assessment was then compared with the pre-surgical calculated maps. In addition, the application of our maps for prediction of progression was studied in a small cohort of 13 newly diagnosed GBM patients undergoing standard chemoradiation and followed up to 19.7 months post therapy. The maps showed two primary enhancement populations: the slow population where contrast clearance from the tissue was slower than contrast accumulation and the fast population where clearance was faster than accumulation. Comparison with histology confirmed the fast population to consist of morphologically active tumor and the slow population to consist of non-tumoral tissues. Our maps demonstrated significant correlation with perfusion-weighted MR data acquired simultaneously, although contradicting examples were shown. Preliminary results suggest that early changes in the fast volumes may serve as a predictor for time to progression. These preliminary results suggest that our high resolution MRI-based delayed enhancement subtraction maps may be applied for clear depiction of tumor and non-tumoral tissues in patients with primary brain tumors and patients with brain metastases.

Lately different and rare genetic forms of Parkinson's disease (PD) have been described. Complete genomic screening has suggested that still undefined multiple genetic factors might underlie the development of PD. The course of PD patients with and without genetic background might be different. We compared the age at onset and progression of PD with (FH) and without (NFH) family history. Two hundred forty PD patients attending the outpatient Movement Disorders Clinic were evaluated. The age of onset (AO), the duration of disease until stage III of Hoehn and Yahr (YST3), until dementia (YDEM) and family history of PD were determined by interview, examination of medical files and of affected family members. Patients with young onset who reported another PD patient among their siblings were tested for parkin mutations. Statistical analysis used ANOVA, Fisher's Least Significant Difference, log-rank and Wilcoxon's tests for Kaplan-Meier survival curves taking stage III and dementia as end-points. Of the 240 patients (age 73.3 +/- 10.9 years), 29 (12%) had positive FH. Six of them carried parkin mutations. The AO was 33.5 +/- 8.1 (range 19-42) years for parkin carriers, 59.3 +/- 11.3 (range 34-76) for FH and 66.5 +/- 11.8 (27-91) years for NFH (P < 0.0001). The three groups were significantly different from each other (alpha = 0.05). Stage III and dementia were reached only in non-parkin patients. YST3 was 12.6 +/- 6.6 years for FH and 6.5 +/- 5.0 years for NFH (P < 0.0001). YDEM was 10.1 +/- 6.0 years for FH versus 4.7 +/- 4.5 years for NFH (P = 0.002). Kaplan-Meier survival analysis revealed faster motor (P = 0.0016) and mental decline (P = 0.02) in NFH versus FH. Our results showed that the AO of PD is younger in patients with FH. Motor and mental deterioration, however, showed a less steep course in familial PD patients.